Dual-function heat indicator and method of manufacture

ABSTRACT

A dual-function heat indicator for monitoring two or more modes of heat exposure is described. A manufacturing process for the dual-function heat indicator is also described. Dual-function heat indicators as described may be useful for monitoring the exposure of host products, with which the dual-function heat indicators may be associated, to cumulative ambient heat exposure and to a peak ambient heat exposure, and for other purposes.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation application of U.S. patentapplication Ser. No. 16/053,253 filed Aug. 2, 2018, which is acontinuation application of U.S. patent application Ser. No. 15/232,468filed Aug. 9, 2016, which is a continuation-in-part application of U.S.patent application Ser. No. 14/943,600 filed Nov. 17, 2015, which is acontinuation application of U.S. patent application Ser. No. 13/893,317filed May 13, 2013, which claims the benefit of U.S. Provisional PatentApplication No. 61/645,889 filed May 11, 2012. The entire contents ofeach of these applications are hereby incorporated by reference in theirentirety.

BACKGROUND

Many commercial products are heat-sensitive and may lose efficacy orquality if they experience excessive ambient heat exposure before theyare used. Examples of heat-sensitive commercial products include certainpharmaceuticals, medical products, and foodstuffs as well as someindustrial products. Accordingly, time-temperature indicators have beenprovided that may monitor the cumulative ambient heat exposure of a hostproduct and signal when a predetermined value that may correlate with adecline in the condition of the host product has been reached. Thesignal may be a color change, for example a darkening of an indicatorarea, and may be generated by a heat-sensing agent such as adiacetylenic compound, or another technology, that integrates the heatexposure, as measured by temperature, over time. Some examples ofheat-sensitive diacetylenic compounds, and of time-temperatureindicators employing them, are described in U.S. Pat. No. 8,067,483 toPrusik et al.; U.S. Patent Application Publication No. 2009/0131718 byBaughman et al.; and U.S. Patent Application Publication No.2011/0086995 by Castillo Martinez et al. Other patents and patentpublications describing various time-temperature indicator technologiesare cited elsewhere herein.

Some host products are also sensitive to short-lived peaks, or spikes,of heat exposure that may not have sufficient cumulative heat value tocause an accompanying time-temperature indicator to signal that a heatexposure limit may have been reached. Some examples of such products arevaccines and other medical products which include a proteinaceous activeingredient.

Accordingly, there is a need for a dual-function heat indicator that mayeffectively monitor cumulative ambient heat exposure and peak ambientheat exposure and provide a clear signal of possible excess heatexposure.

Various proposals are known for indicators that may signal past exposureto temperatures exceeding a threshold. For example, U.S. Pat. No.5,709,472, and its divisional patent, U.S. Pat. No. 6,042,264, both toPrusik et al., describe and claim a time-temperature indicator label formeasuring the length of time to which a product has been exposed to atemperature above a pre-determined temperature. Also, U.S. Pat. No.7,517,146 to Smith et al. describes an excess temperature indicator thatmay provide a visual indication of past exposure of perishable, maturingand other host products to an elevated temperature exceeding a thresholdtemperature.

Further, U.S. Pat. No. 5,057,434 to Prusik et al. (“Prusik et al. '434”herein) relates to an improved time-temperature indicator device usefulin monitoring the environmental exposure of products that undergoprogressive quality changes in response to such exposures. See, e.g.,column 1, lines 5-8 of Prusik et al. '434. As described, a cumulativetime-temperature indicator and a threshold indicator may be integratedinto a single device. Further, the device may gradually and irreversiblydevelop color as a function of time and temperature and more closelymonitor the actual condition of a deteriorative product than does asingle indicator, See, e.g., abstract of Prusik '434. The capabilitiesof the system may be enhanced by a barrier layer that delays the colordevelopment action. See, e.g., column 9, lines 25-33.

SUMMARY

While the heat exposure indicators described in the foregoing backgroundmay be effective for their intended purposes, a need exists for adual-function heat indicator that may monitor both cumulative ambientheat exposure and peak ambient heat exposure, and which has enhancedproperties.

Some commercial products are particularly sensitive to heat and have asmall heat capacity so that even brief peaks of excessive heat may bedamaging. For example, vaccines are typically packaged in small vialsincluding individual dosages and readily lose potency if theirimmunogenic proteins are subjected to excessive heat.

Accordingly, a dual-function heat indicator that may signal cumulativeambient heat exposure and exposure to an ambient heat peak of briefduration would be useful to monitor vaccines and other products forpotentially damaging heat exposure.

One example embodiment of the invention is a dual-function heatindicator for monitoring cumulative ambient heat exposure and peakambient heat exposure. The dual-function heat indicator may include asubstrate, a cumulative exposure indicator supported by the substrateand a peak exposure indicator supported by the substrate. The cumulativeexposure indicator may be supported in a viewable, layeredconfiguration, and may be color-changeable in response to cumulativeambient heat exposure. The peak exposure indicator may also be supportedby the substrate in a viewable, layered configuration.

The peak exposure indicator may include a first reactant, a secondreactant and a meltable solid. The first reactant may be chemicallyco-reactable with the second reactant to provide a color change and themeltable solid may physically separate the first reactant from thesecond reactant. The color-changing chemical reaction may be induced inresponse to an ambient heat exposure peak, which may be a peak thatexceeds the melting point of the meltable solid. For example, melting ofthe meltable solid caused by the ambient heat exposure peak may bringthe first reactant into contact with the second reactant. Such adual-function heat indicator may indicate cumulative ambient heatexposure and/or peak ambient heat exposure by changing color. Someembodiments may change color in response to any of: cumulative ambientheat exposure reaching a predetermined value; a peak ambient heatexposure event; a combination of the two events; and a combination oftwo partial events that have a sufficient additive effect. Use ofchemical reactants to provide a color change may enable the peakexposure indicator to respond quickly to a relatively brief ambient heatexposure peak, and with appropriate selection of reactants, with astrong color change.

The dual-function heat indicator may also include a viewable active areawherein the cumulative exposure indicator and the peak exposureindicator are viewable with the optical densities of the viewedindicators combined. Thus, the outputs of the cumulative exposureindicator and the peak exposure indicator may be integrated into asingle display.

In some example embodiments, the peak exposure indicator may include apeak indicator layer of the dual-function heat indicator and the firstreactant and the second reactant may be particulate and dispersed in thepeak indicator layer. Including the first reactant and the secondreactant, and optionally, the meltable solid in the same layer of thedual-function heat indicator may help provide a quick response as aresult of the proximity of the reactants.

The cumulative exposure indicator may be transparent prior to changingcolor and may be configured in a first layer of the dual-function heatindicator and the peak exposure indicator may be configured in a secondlayer of the dual-function heat indicator. The second layer may bedisposed between the cumulative exposure indicator and the substrate,and the peak exposure indicator may be viewable through the cumulativeexposure indicator when the latter is transparent.

The peak exposure indicator may be configured in a first layer of thedual-function heat indicator, and the cumulative exposure indicator maybe opaque and become translucent or transparent with exposure to heatover time and may be configured in a second layer of the dual-functionheat indicator. The second layer may be disposed between the peakexposure indicator and the substrate, and the cumulative exposureindicator may be viewable through the peak exposure indicator when thelatter is transparent or translucent.

In another example embodiment of the dual-function heat indicator, thecumulative exposure indicator is configured in one layer and the peakexposure indicator is disposed in the same layer as the cumulativeexposure indicator.

In a further example embodiment of the invention, a meltable coloredmaterial that has a small particle size and is initially light-coloreddue to light scattering, and which darkens upon melting, may replace thefirst reactant and the second reactant. Alternatively, the material mayreveal or obscure a background color upon melting, resulting in a changeof the visual appearance of an indicator.

Another example embodiment of the invention is a heat indicator formonitoring ambient heat exposure traversing a threshold temperature thatemploys a coalescable particulate colored material that has a smallparticle size and is initially light-colored due to light scattering,and which darkens in response to an ambient heat exposure eventtraversing the threshold temperature. The threshold temperature may be apeak temperature, a freezing temperature or another suitabletemperature.

Another example embodiment of the invention is a method of making adual-function heat indicator for monitoring cumulative ambient heatexposure and peak ambient heat exposure. Optionally, the dual-functionheat indicator may be the example embodiment described previouslyherein. The method may include applying a liquid composition including acumulative heat-sensing agent to a substrate. The cumulativeheat-sensing agent may be color-changeable in response to cumulativeambient heat exposure and may be transparent prior to changing color.Further, the method may include drying the liquid composition on thesubstrate to provide a dried composition, without changing the color ofthe heat-sensing agent, and incorporating a peak exposure indicatorcomposition in the liquid composition. The peak exposure indicatorcomposition may include a first reactant, a second reactant and ameltable solid.

Drying may be conducted at a relatively low temperature, for example, atemperature below the melting-point of the meltable solid, such as atemperature below about 40° C. or below about 30° C. Forced convection,control of the humidity of the air or gas flow, and/or limiting theduration of the drying may optionally be employed to assist drying andavoid changing the color of the heat-sensing agent. Other useful dryingtechniques that may be employed and which may be performed at a suitablylow temperature include radiation curing, for example using ultravioletlight or electron beam energy.

As an alternative to incorporating a peak exposure indicator compositionin the liquid composition, the method may include supporting a peakexposure indicator including a first reactant, a second reactant and ameltable solid on the substrate, prior to the application of the liquidcomposition, and applying the liquid composition over the peak exposureindicator on the substrate.

In some example embodiments of the method, the first reactant and thesecond reactant may be chemically co-reactable to provide a colorchange, the meltable solid may physically separate the first reactantfrom the second reactant in the dried composition, or in thesubstrate-supported peak exposure indicator, and/or the color-changingchemical reaction may be induced in response to an ambient heat exposurepeak.

Another example embodiment may include applying the peak exposureindicator composition to a discrete area of the substrate prior toapplying the liquid composition, and applying the liquid composition tothe entire area of the peak exposure indicator. The substrate may bear acoating of the peak exposure indicator composition and the coating may,optionally, extend over the entire area of the substrate.

An alternative method of manufacturing may have the cumulative and peakindicators prepared separately as described above, and then beingcombined by lamination.

In practicing some example embodiments of the invention, the firstreactant and the second reactant may be particulate and the liquidcomposition may include an aqueous dispersion of the first reactant, thesecond reactant and the meltable solid.

In one example embodiment of the dual-function heat indicator formonitoring cumulative ambient heat exposure and peak ambient heatexposure, the dual-function heat indicator may include a substrate, acumulative exposure indicator supported by the substrate in a viewable,layered configuration, the cumulative exposure indicator beingcolor-changeable in response to cumulative ambient heat exposure, and apeak exposure indicator supported by the substrate in a viewable,layered configuration, the peak exposure indicator may include a firstreactant, a second reactant and a meltable solid, the first reactantbeing chemically co-reactable with the second reactant to provide acolor change, the meltable solid physically separating the firstreactant from the second reactant, and the color-changing chemicalreaction being induced in response to an ambient heat exposure peaktemperature exceeding the melting point of the meltable solid whereinthe dual-function heat indicator indicates at least one of cumulativeambient heat exposure and peak ambient heat exposure by changing color.

Optionally the example embodiment of the dual-function heat indicatormay include a viewable active area wherein the cumulative exposureindicator and the peak exposure indicator are viewable in the activearea with the optical densities of the viewed indicators combined.Further, in the example embodiment of the dual-function heat indicatorthe peak exposure indicator may include a peak indicator layer where thefirst reactant and the second reactant are particulate and aredispersed.

Alternatively, the example embodiment of the dual-function heatindicator may include a cumulative exposure indicator which may betransparent prior to changing color and is configured in a first layerwhile the peak exposure indicator is configured in a second layer, thesecond layer being disposed between the cumulative exposure indicatorand the substrate and the peak exposure indicator being viewable throughthe cumulative exposure indicator when transparent. Further, optionally,in the example embodiment of the dual-function heat indicator thecumulative exposure indicator may be configured in one layer and thepeak exposure indicator may be disposed in the same layer as thecumulative exposure indicator.

Optionally in the example embodiment of the dual-function heat indicatorthe substrate may be configured to be conformable with a host productwhich may enable the dual-function heat indicator to be attachable tothe host product, optionally, by bearing a pressure-sensitive adhesivelayer. Further, optionally, in the example embodiment of thedual-function heat indicator the first reactant and the second reactantmay be solid and the meltable solid may further include a thermalsensitizer to modify the melting point of the peak meltable solid.Further, the meltable solid may include a binder. Alternatively, in theexample embodiment of the dual-function heat indicator the firstreactant may include a color former and the second reactant may includea color developer and wherein, optionally, the color former or the colordeveloper, or both the color former and the color developer, areinitially colorless.

Optionally, in the example embodiment of the dual function heatindicator the color developer may be chosen from a group consisting ofan oil-soluble reducing agent, oxalic acid, phosphite ester,hydroxybenzoic acid ester, hydrohydroquinone, a hydroquinone derivativesuch as dimethyhydroquinone, di-tert-butyl hydro quinone,dialkylhydroquinone, 3-ethoxyphenol, 1,2-diethyl-3-hydroxybenzene,1,3-diethyl-2-hydroxybenzene, 2,2′-methylenebis(3,4,6 trichlorophenol);meltable, or sensitizer-soluble, primary and secondary amines having lowwater solubility, for example, 4-butyl-aniline, phenol derivatives,organic acids, acid clays, reactive acid hectorite clay, phenolicresins, phenol-acetylene resins, polyvalent metallic salts of phenolicresins, zinc-including modified alkyl phenolic resin, zinc salicylate,zinc salicylate resin, 4,4′-isopropylidenebisphenol (also known asbisphenol A), 1,7-di(hydroxyphenylthio)-3,5-dioxaheptane, 4-hydroxyethylbenzoate, 4-hydroxydimethyl phthalate, monobenzyl phthalate,bis-(4-hydroxy-2-methyl-5-ethylphenyl)sulfide,4-hydroxy-4′-isopropoxydiphenyl sulfone,4-hydroxyphenylbenzenesulfonate, 4-hydroxybenzoyloxybenzylbenzoate,bis-(3-1-butyl-4-hydroxy-6-methylphenyl)sulfone, p-tert-butylphenol, orpolymers based on bisphenol A.

Further, alternatively, in the example embodiment of the dual functionheat indicator the color former may be chosen from a group including3,3-bis(p-dimethylaminophenyl)-phthalide,3,3-bis(p-dimethylaminophenyl)-6-dimethylaminophthalide (crystal violetlactone), 3,3-bis(p-dimethylaminophenyl)-6-diethylaminophthalide,3,3-bis(p-dimethylaminophenyl)-6-chlorophthalide,3,3-bis(p-dibutylaminophenyl)-phthalide,3-(N—N-diethylamino)-5-methyl-7-(N,N-dibenzylamino) fluoran,3-dimethylamino-5,7-dimethylfluoran, 3-diethylamino-7-methylfluoran,3-(2′-hydroxy-4′-dimethylaminophenyl)-3-(2′[-methoxy-5′-chlorophenyl)phthalide,3-(2′-hydroxy-4′-dimethylaminophenyl)-3-(2′-methoxy-5′-nitrophenyl-phthalide,3-(2′-hydroxy-4′-diethylaminophenyl)-3-(2′-methoxy-5′-methylphenyl)phthalide,3-(2′-methoxy-4′-dimethylaminophenyl)-3-(2′-hydroxy-4′-chloro-5′-methylphenyl)-phthalide,benzoylleuco methylene blue, malachite green lactone,N-2,4,5-trichlorophenylleuco auramine,3-diethylamino-6-methyl-7-chlorofluoran, 3,6-bis(diethylamino)fluoran-γ-(4′-nitro)-anilinolactam,3-diethylamino-6-methyl-7-anilinofluoran,3-(N-ethyl-N-isoamylamino)-6-methyl-7-anilinofluoran,3-cyclohexylamino-6-chlorofluoran or 3-diethylamino-6,8-dimethylfluoran.

Further in the example embodiment of the dual-function heat indicatorthe cumulative exposure indicator may include at least one thermallysensitive, polymerizable diacetylenic compound containing at least twoconjugated acetylenic groups. Furthermore, the cumulative heat exposurecolor change may be irreversible and occur after a predeterminedcumulative heat exposure. Optionally the example embodiment of thedual-function heat indicator may include a freeze indicator wherein thefreeze indicator is supported by the substrate and wherein, optionally,the freeze indicator may be transparent before activation by exposure toa freezing temperature, may be supported on the cumulative exposureindicator and the cumulative exposure indicator or may be viewablethrough the freeze indicator.

Optionally in the example embodiment of the dual function heat indicatorthe substrate may include a printed reference surface. In someembodiments, the reference surface—before or after being printed—mayhave a color such as blue or gray, which color may be derived from thecolor of the substrate or from the ink printed on the surface. In someembodiments, the substrate is similar in color or hue to the referencesurface, or the substrate is darker than the reference surface. Thesubstrate may be or may include a synthetic sheet or film furthercomprised of polyethylene, polypropylene, polycarbonate, polyester,polyamide, polyurethane, polyvinyl chloride, polyvinylidene chloride,cellulose-derived materials, aluminum, aluminum foil, paper, or coatedpaper. Alternatively, substrate may be clear or white. Optionally in theexample embodiment the substrate may be a clear polyester film. In theexample embodiment of the dual function heat indicator the peakindicator may include a pre-manufactured thermal paper or film having anormal color change activation temperature of greater than 60° C.

In some embodiments, a cumulative exposure indicator comprises amaterial that is removed or dissolved over time with exposure to heat.The removable material may be removed by an acid or a base that reactswith the material at a predictable rate. Moreover, the acid or base maybe separated from the removable material by a barrier material so tobetter control the rate at which the acid or base interacts with theremovable material.

In some embodiments of a cumulative exposure indicator where thesubstrate comprises or includes aluminum foil or a thin layer ofaluminum, an etchant may be included that is configured to etch away thealuminum over time with exposure to heat so as to reveal the underlyingsubstrate. The cumulative exposure indicator may include a barriercoating configured to initially separate the etchant from the layer ofaluminum and to control the rate at which the etchant reacts with thelayer of aluminum. The etchant may be contained within apressure-sensitive laminating adhesive layer.

Suitable etchants include nitric acid, hydrochloric acid, picric acid,ethanol, potassium hydroxide, copper sulfate, sodium thiosulfate,potassium metabisulfite, copper chlorite, copper chlorate, copperammonium, ammonia, hydrogen peroxide, hydrofluoric acid, phosphoricacid, and mixtures thereof. Suitable etchants can include mixtures of1-5% HNO₃, 65-75% H₃PO₄, 5-10% CH₃COOH, using H₂O dilution to define theetch rate at given temperature; mixtures of nitric acid, hydrochloricacid, and hydrofluoric acid; and mixtures of distilled water, nitricacid, and hydrofluoric acid. Other etchants include Keller's reagent andKroll's reagent, ASTM No. 30, Adler etchant, carpenters stainless steeletch, Kalling's No. 2, Klemm's reagent, Nital, Marble's reagent,Murakami's, Picral, and Vilella's reagent, TECHNIETCH A180. Etchants canalso include the following: a mixture of H₂O and HF; a mixture of HCl,HNO₃, and H₂O; diluted or concentrated HCl; a mixture of H₃PO₄, HNO₃,and HAc; a mixture of H₃PO₄, HAc, HNO₃, and H₂O; a mixture of H₃PO₄,H₂O₂, and H₂O; a mixture of H₃PO₄, H₂O, and glycerin; a mixture of HClO₄and HAc; a mixture of FeCl₃ and H₂O; a 10% solution of K₃Fe(CN)₆; amixture of KOH, K₃Fe(CN)₆, and K₂B₄O₇.4H₂O; a mixture of KMnO₄, NaOH,and H₂O; a mixture of NH₄OH, H₂O₂, and H₂O; a 20% solution of NH₄SO₄; adilute or concentrated solution of NaOH; an 8-10% solution of KOH; CCl₄;or a 10% solution of Br₂ and MeOH.

A barrier coating may be positioned between two layers of the cumulativeexposure indicator. In some embodiments, the barrier coating ispositioned between the etchant discussed above and the peak exposureindicator so as to reduce or prevent the etchant from possiblytriggering the peak exposure indicator.

The example embodiment of the dual function heat indicator may includean activator applied to the pre-manufactured thermal paper or filmconfigured to lower the color change activation temperature of thepre-manufactured thermal paper or film to below 60° C. Optionally, theactivator may be an organic solvent chosen from a group consisting ofheptadecanol, 4-methoxyphenol, pentadecanol, 2,4-di-tert-butyl phenol orbenzophenone.

Alternatively in the example embodiment of the dual function indicatorthe activator may be chosen to have a melting point that isapproximately the same as a desired predetermined peak ambienttemperature threshold that is indicated by the peak exposure indicator.The example embodiment of the dual function heat indicator may furtheroptionally include a barrier separating the activator from thepre-manufactured thermal paper or film, the barrier configured to allowthe activator to contact the thermal paper in response to an ambientheat exposure peak temperature greater than a predetermined peaktemperature, but less than the normal activation temperature of thethermal paper. Further, the barrier may be a meltable solid.

Optionally, in the example embodiment of the dual-function heatindicator the peak exposure indicator may have a response temperaturechosen from the group consisting of in the range from about 30° C. toabout 50° C., in the range of from about 40° C. to about 60° C., in therange of from about 30° C. to about 40° C., in the range of from about40° C. to about 50° C., in the range of from about 50° C. to about 60°C., in the range of from about 30° C. to about 35° C., in the range offrom about 35° C. to about 40° C., in the range of from about 40° C. toabout 45° C., in the range of from about 45° C. to about 50° C., in therange of from about 50° C. to about 55° C., in the range of from about55° C. to about 60° C., about 30° C., about 35° C., about 40° C., about45° C., about 50° C., about 55° C., of and about 60° C.

In another example embodiment of the dual-function heat indicator formonitoring cumulative ambient heat exposure and peak ambient heatexposure, the dual-function heat indicator includes a substrate, acumulative exposure indicator supported by the substrate in one viewablelayer of the dual-function heat indicator, the cumulative exposureindicator being color-changeable or exhibiting a change in appearance inresponse to cumulative ambient heat exposure, and a peak exposureindicator supported by the substrate in another viewable, layer of thedual-function heat indicator, the peak exposure indicator comprising ameltable particulate colored material. In some embodiments, the meltableparticulate colored material has an average particle size imbuing themeltable particulate colored material with a light color, the lightcolor being attributable to scattering of visible light by the meltablecolored material particles, wherein melting of the meltable particulatecolored material causes the peak exposure indicator to change its visualappearance, the change in appearance being induced by an ambient heatexposure peak reaching a temperature exceeding the melting point of themeltable particulate colored material, and wherein the dual-functionheat indicator indicates cumulative ambient heat exposure or peakambient heat exposure by changing color. Light scattering may be causedor influenced by, in some embodiments, air gaps between the meltableparticulate material that is suspended in a binder material. In someembodiments, the meltable particulate material allows the cumulativeexposure indicator to be seen through the peak exposure indicator, whichmeans that prior to activation, the meltable particulate material allowsfor the passage of light but a temperature above a predeterminedthreshold causes the peak exposure indicator to change in appearance andobscure the underlying cumulative exposure indicator.

Optionally in the example embodiment of the dual heat indicator thechange in appearance of the peak exposure indicator may be caused by themeltable particulate colored material darkening in color or may becaused by the melting of the meltable particulate material revealing abackground or may be caused by the melting of the meltable particulatematerial obscuring a background. Alternatively, in the exampleembodiment of the dual-function heat indicator the meltable particulatecolored material includes a meltable solid and a dye dissolved in themeltable solid.

In yet another example embodiment, a heat event indicator for monitoringambient heat exposure to a temperature traversing a thresholdtemperature includes a substrate and a coalesceable particulate coloredmaterial supported by the substrate wherein the coalesceable particulatecolored material has an average particle size imbuing the coalesceableparticulate colored material with a light color, the light color beingattributable to scattering of visible light by the coalesceable coloredmaterial particles wherein coalescence of the coalesceable particulatecolored material causes the coalesceable particulate colored material todarken in color, the darkening being induced by an ambient heat exposureevent reaching a temperature traversing the threshold temperature andwherein the heat event indicator indicates the occurrence of the ambientheat exposure event by changing color. Alternatively in this exampleembodiment of the heat event indicator the threshold temperature may bea peak temperature and the coalesceable particulate colored material maybe meltable and melts in response to the ambient heat exposure event.Optionally, in the example embodiment of the heat event indicator thethreshold temperature may be a freezing temperature, the heat eventindicator including a dispersion of the coalesceable particulate coloredmaterial in aqueous liquid medium, wherein the dispersion collapses andthe coalesceable particulate colored material coalesces in response tothe ambient heat exposure event.

Further in another example embodiment of the dual-function heatindicator or heat event indicator the host product and the dual-functionheat indicator or the heat event indicator may be associated to monitorthe host product for heat exposure; the host product, optionally, beinga medical product comprising a heat-sensitive proteinaceous component.

In yet another example embodiment of the dual function heat indicator amethod of making a dual-function heat indicator for monitoringcumulative ambient heat exposure and peak ambient heat exposure,optionally, being a dual-function heat indicator includes applying aliquid composition comprising a cumulative heat-sensing agent to asubstrate, the cumulative heat-sensing agent being color-changeable inresponse to cumulative ambient heat exposure and being transparent priorto changing color, and drying the liquid composition on the substrate toprovide a dried composition, without changing the color of theheat-sensing agent, incorporating a peak exposure indicator compositionin the liquid composition, the peak exposure indicator compositioncomprising a first reactant, a second reactant and a meltable solid, orsupporting a peak exposure indicator comprising a first reactant, asecond reactant and a meltable solid on the substrate prior to theapplication of the liquid composition and applying the liquidcomposition over the peak exposure indicator on the substrate whereinthe first reactant and the second reactant are chemically co-reactableto provide a color change, the meltable solid physically separates thefirst reactant from the second reactant in the dried composition or inthe substrate-supported peak exposure indicator, and the color-changingchemical reaction is induced in response to an ambient heat exposurepeak. Optionally the example embodiment of the method of making the dualheat indicator may include applying the peak exposure indicatorcomposition to a discrete area of the substrate prior to applying theliquid composition and applying the liquid composition to the entirearea of the peak exposure indicator. Alternatively, the exampleembodiment of the method of making the dual heat indicator may includethe substrate bearing a coating of the peak exposure indicatorcomposition, the coating optionally extending over the entire area ofthe substrate. Optionally, in the example embodiment of the method ofmaking the dual heat indicator the first reactant and second reactantare both particulate and the liquid composition includes an aqueousdispersion of the first reactant, the second reactant and the meltablesolid.

In yet another example embodiment, the method for treating a thermalsubstrate configured to respond to an ambient temperature above a firstpredetermined threshold by changing color, the method includes applyingan activator to the thermal substrate, the activator configured to causethe thermal substrate to change color at an ambient temperature above asecond predetermined threshold, the second predetermined thresholdsubstantially lower than the first predetermined threshold. Optionally,in the example embodiment the method may include coating a printablesurface of the thermal substrate with the activator wherein theactivator includes a meltable solid. Alternatively, in the exampleembodiment of the method the thermal substrate may include a thermalcoating further including a first reactant and a second reactant whichare chemically co-reactable to provide a color change, wherein the colorchange is a chemical reaction being induced in response to a peaktemperature exceeding the melting point of the activator. Optionally, inthe example embodiment of the method the first reactant may include acolor former and the second reactant comprises a color developer andwherein optionally, the color former or the color developer, or both thecolor former and the color developer are initially colorless. The colordeveloper may be chosen from a group including an oil-soluble reducingagent, oxalic acid, phosphite ester, hydroxybenzoic acid ester,hydrohydroquinone, a hydroquinone derivative such asdimethyhydroquinone, di-tert-butyl hydro quinone, dialkylhydroquinone,3-ethoxyphenol, 1,2-diethyl-3-hydroxybenzene,1,3-diethyl-2-hydroxybenzene, 2,2′-methylenebis(3,4,6 trichlorophenol);meltable, or sensitizer-soluble, primary and secondary amines having lowwater solubility, for example, 4-butyl-aniline, phenol derivatives,organic acids, acid clays, reactive acid hectorite clay, phenolicresins, phenol-acetylene resins, polyvalent metallic salts of phenolicresins, zinc-including modified alkyl phenolic resin, zinc salicylate,zinc salicylate resin, 4,4′-isopropylidenebisphenol (also known asbisphenol A), 1,7-di(hydroxyphenylthio)-3,5-dioxaheptane, 4-hydroxyethylbenzoate, 4-hydroxydimethyl phthalate, monobenzyl phthalate,bis-(4-hydroxy-2-methyl-5-ethylphenyl)sulfide,4-hydroxy-4′-isopropoxydiphenylsulfone, 4-hydroxyphenylbenzenesulfonate,4-hydroxybenzoyloxybenzylbenzoate,bis-(3-1-butyl-4-hydroxy-6-methylphenyl)sulfone, p-tert-butylphenol, orpolymers based on bisphenol A. The color former may be chosen from agroup including 3,3-bis(p-dimethylaminophenyl)-phthalide,3,3-bis(p-dimethylaminophenyl)-6-dimethylaminophthalide (crystal violetlactone), 3,3-bis(p-dimethylaminophenyl)-6-diethylaminophthalide,3,3-bis(p-dimethylaminophenyl)-6-chlorophthalide,3,3-bis(p-dibutylaminophenyl)-phthalide,3-(N—N-diethylamino)-5-methyl-7-(N,N-dibenzylamino) fluoran,3-dimethylamino-5,7-dimethylfluoran, 3-diethylamino-7-methylfluoran,3-(2′-hydroxy-4′-dimethylaminophenyl)-3-(2′[-methoxy-5′-chlorophenyl)phthalide,3-(2′-hydroxy-4′-dimethylaminophenyl)-3-(2′-methoxy-5′-nitrophenyl-phthalide,3-(2′-hydroxy-4′-diethylaminophenyl)-3-(2′-methoxy-5′-methylphenyl)phthalide,3-(2′-methoxy-4′-dimethylaminophenyl)-3-(2′-hydroxy-4′-chloro-5′-methylphenyl)-phthalide,benzoylleuco methylene blue, malachite green lactone,N-2,4,5-trichlorophenylleuco auramine,3-diethylamino-6-methyl-7-chlorofluoran, 3,6-bis(diethylamino)fluoran-γ-(4′-nitro)-anilinolactam,3-diethylamino-6-methyl-7-anilinofluoran,3-(N-ethyl-N-isoamylamino)-6-methyl-7-anilinofluoran,3-cyclohexylamino-6-chlorofluoran or 3-diethylamino-6,8-dimethylfluoran. Optionally, in the example embodiment of themethod it may further include barrier which prevents direct contactbetween the activator and the thermal coating and wherein the barrier isa meltable solid with a melting point of about the second thresholdtemperature, wherein an ambient temperature above the secondpredetermined threshold causes melting of the barrier triggering thereaction between the first reactant and second reactant to chemicallyco-react and provide a color change. Optionally in the exampleembodiment of the method the meltable solid is chosen to have a meltingpoint that is approximately the same as a desired predetermined peakambient temperature threshold that is indicated by the peak exposureindicator. Alternatively in the example embodiment of the method thethermal substrate may be pre-manufactured thermal paper orpre-manufactured thermal film. Optionally, in the example embodiment ofthe method the activator may be an organic solvent, preferably chosenfrom a group including heptadecanol, 4-methoxyphenol, pentadecanol,2,4-di-tert-butyl phenol or benzophenone, and more preferably theactivator is benzophenone. Alternatively in the example embodiment ofthe method the ambient temperature above the second predeterminedthreshold may cause melting of the activator triggering the reactionbetween the first reactant and second reactant to chemically co-reactand provide a color change.

In yet a further example embodiment a peak heat indicator includes apre-manufactured thermal substrate normally configured to respond to anambient temperature above a first predetermined threshold by changingcolor, and an activator applied to the thermal substrate and configuredto interact with the pre-manufactured thermal substrate so that thepre-manufactured substrate changes color to respond to an ambienttemperature above a second predetermined threshold by changing color,the second predetermined threshold being substantially lower than thefirst predetermined threshold. Optionally in the example embodiment ofthe peak heat indicator the activator may include a meltable solidhaving a melting point approximately the same as the secondpredetermined temperature, wherein an ambient temperature above thesecond predetermined threshold causes melting of the activatortriggering the reaction between the first reactant and second reactant,causing them to chemically co-react and provide a color change.Alternatively in the example embodiment of the peak indicator themeltable solid may be chosen to have a melting point that isapproximately the same as a desired predetermined peak ambienttemperature threshold that is indicated by the peak exposure indicator.Optionally in the example embodiment of the peak indicator the thermalsubstrate may include a thermal coating further include a first reactantand a second reactant which are chemically co-reactable to provide acolor change wherein the color, change is a chemical reaction beinginduced in response to a peak temperature exceeding the melting point ofthe activator. Alternatively in the example embodiment of the peakindicator the first reactant comprises a color former and the secondreactant comprises a color developer and wherein optionally, the colorformer or the color developer, or both the color former and the colordeveloper are initially colorless. Optionally in the example embodimentof the peak indicator the color developer may be chosen from a groupincluding an oil-soluble reducing agent, oxalic acid, phosphite ester,hydroxybenzoic acid ester, hydrohydroquinone, a hydroquinone derivativesuch as dimethyhydroquinone, di-tert-butyl hydro quinone,dialkylhydroquinone, 3-ethoxyphenol, 1,2-diethyl-3-hydroxybenzene,1,3-diethyl-2-hydroxybenzene, 2,2′-methylenebis(3,4,6 trichlorophenol);meltable, or sensitizer-soluble, primary and secondary amines having lowwater solubility, for example, 4-butyl-aniline, phenol derivatives,organic acids, acid clays, reactive acid hectorite clay, phenolicresins, phenol-acetylene resins, polyvalent metallic salts of phenolicresins, zinc-including modified alkyl phenolic resin, zinc salicylate,zinc salicylate resin, 4,4′-isopropylidenebisphenol (also known asbisphenol A), 1,7-di(hydroxyphenylthio)-3,5-dioxaheptane, 4-hydroxyethylbenzoate, 4-hydroxy dim ethyl phthalate, monobenzyl phthalate,bis-(4-hydroxy-2-methyl-5-ethylphenyl)sulfide,4-hydroxy-4′-isopropoxydiphenylsulfone, 4-hydroxyphenylbenzenesulfonate,4-hydroxybenzoyloxybenzylbenzoate,bis-(3-1-butyl-4-hydroxy-6-methylphenyl)sulfone, p-tert-butylphenol, orpolymers based on bisphenol A.

Optionally in the example embodiment of the peak indicator the colorformer is chosen from a group consisting of:3,3-bis(p-dimethylaminophenyl)-phthalide,3,3-bis(p-dimethylaminophenyl)-6-dimethylaminophthalide (crystal violetlactone), 3,3-bis(p-dimethylaminophenyl)-6-diethylaminophthalide,3,3-bis(p-dimethylaminophenyl)-6-chlorophthalide,3,3-bis(p-dibutylaminophenyl)-phthalide,3-(N—N-diethylamino)-5-methyl-7-(N,N-dibenzylamino) fluoran,3-dimethylamino-5,7-dimethylfluoran, 3-diethyl amino-7-methylfluoran,3-(2′-hydroxy-4′-dimethylaminophenyl)-3-(2′[-methoxy-5′-chlorophenyl)phthalide,3-(2′-hydroxy-4′-dimethylaminophenyl)-3-(2′-methoxy-5′-nitrophenyl-phthalide,3-(2′-hydroxy-4′-diethylaminophenyl)-3-(2′-methoxy-5′-methylphenyl)phthalide,3-(2′-methoxy-4′-dimethylaminophenyl)-3-(2′-hydroxy-4′-chloro-5′-methylphenyl)-phthalide,benzoylleuco methylene blue, malachite green lactone,N-2,4,5-trichlorophenylleuco auramine, 3-diethylamino-6-methyl-7-chlorofluoran, 3,6-bis(diethylamino)fluoran-γ-(4′-nitro)-anilinolactam,3-diethylamino-6-methyl-7-anilinofluoran,3-(N-ethyl-N-isoamylamino)-6-methyl-7-anilinofluoran,3-cyclohexylamino-6-chlorofluoran or 3-diethylamino-6,8-dimethylfluoran. Alternatively in the example embodiment ofthe peak indicator the peak heat indication may further include abarrier configured to prevent direct contact between the activator andthe thermal coating wherein the barrier is a meltable solid. Optionallyin the example embodiment of the peak indicator the thermal substrate ispre-manufactured thermal paper or pre-manufactured thermal film.Alternatively in the example embodiment of the peak indicator theactivator is an organic solvent, preferably chosen from a groupincluding heptadecanol, 4-methoxyphenol, pentadecanol, 2,4-di-tert-butylphenol or benzophenone, and more preferably benzophenone.

BRIEF DESCRIPTION OF THE FIGURES

Some example apparatus embodiments of the invention, and exampleprocedures for making and using one or more example embodiments, aredescribed in detail herein and by way of example, with reference to theaccompanying drawings (which are not necessarily drawn to scale withregard to any internal or external structures shown) and in which likereference characters designate like elements throughout the severalviews, and in which:

FIG. 1 is a plan view of two example dual-function heat-indicators,according to an example embodiment of the invention, arrangedside-by-side on a support liner;

FIG. 1A is a plan view of two dual-function heat-indicators with aprintable margin according to the example embodiment of the inventionarranged side-by-side on a support liner;

FIG. 2 is a sectional view on the line 2-2 of one example embodiment ofone of the example dual-function heat indicators shown in FIG. 1;

FIG. 2A is a sectional view on the line 2A-2A of one example embodimentof one of the example dual-function heat indicators with a printablemargin shown in FIG. 1A;

FIG. 3 is a view similar to FIG. 2 of another example embodiment of theexample dual-function heat indicator shown in FIG. 1; and

FIG. 4 is a view similar to FIG. 2 of a further example embodiment ofthe example dual-function heat indicator shown in FIG. 1; and

FIG. 5 is a view similar to FIG. 2 of a further example embodiment ofthe example dual-function heat indicator shown in FIG. 1; and

FIG. 6 is a view similar to FIG. 2 of a further example embodiment ofthe example dual-function heat indicator shown in FIG. 1; and

FIG. 7 is a view similar to FIG. 2 of a further example embodiment ofthe example dual-function heat indicator shown in FIG. 1; and

FIG. 8 is a view similar to FIG. 2 of a further example embodiment ofthe example dual-function heat indicator shown in FIG. 1.

FIG. 9 is a plan view of another example of a dual-functionheat-indicator, according to an example embodiment of the invention.

FIG. 10 is a plan view of yet another example of a dual-functionheat-indicator, according to an example embodiment of the invention.

FIGS. 10A-10M illustrate variations of the embodiment illustrated inFIG. 10.

FIG. 11 is a cross sectional view of an example manufactured dual heatindicator prototype discussed in Example 1 herein.

FIG. 12 is a table, as it pertains to Example 1 herein, showing theoptical density measurements of the active region in the cumulativeindicator only, the dual indicator, and the thermal paper constructiononly, at 90° C. during various time intervals.

FIG. 13 is a table, as it pertains to Example 1 herein, showing theoptical density measurements of the active region in the cumulativeindicator only, the dual indicator, and the thermal paper constructiononly, at 80° C. during various time intervals.

FIG. 14 is a table, as it pertains to Example 1 herein, showing theoptical density measurements of the active region in the cumulativeindicator only, the dual indicator, and the thermal paper constructiononly, at 50° C. during various time intervals.

FIG. 15 is a table, as it pertains to Example 1 herein, showing theoptical density measurements of the active region in the cumulativeindicator only, the dual indicator, and the thermal paper constructiononly, at 37° C. during various time intervals.

FIG. 16 is a table, as it pertains to Example 2 herein, showing theoptical density measurements of the active region in the cumulativeindicator (similar to HEATmarker VVM14), the dual heat indicator, andthe peak indicator (DEGmarker 40), between 25-45° C.

FIG. 17 shows the test cards, as they pertain to Example 2 herein,showing the appearance of the cumulative indicator (similar toHEATmarker VVM14), the dual heat indicator, and the peak indicator(DEGmarker 40) at no heat and heated to 45° C.

FIG. 18 is a table, as it pertains to Example 2, showing the colorappearance of the active region in comparison between the dual heatindicator (VVM14-equivalent with DEGmarker 40) and dual heat indicator(VVM14-equivalent with DEGmarker 45).

FIG. 19 is a table, as it pertains to Example 4, listing the sample,vendor, product, type, initial static sensitivity, and appearance of theactive region of the samples after 40 min at 43° C.

DETAILED DESCRIPTION

Vaccines are a cost-effective health intervention that may save millionsof lives globally. However, difficulties may occur in protecting vaccinesupplies from temperature excesses during storage and distribution,particularly, but not exclusively, in low and middle income countries inhot climatic regions. Unless a monitoring device is employed, a medicaltechnician in the field, wishing to administer a vaccine, has no way ofdistinguishing between vials containing still-potent vaccine dosagesfrom those that may have lost potency due to heat exposure.

The proteins that are usually the active constituents of vaccines arecomplex molecules that may have sophisticated three-dimensionalconformations, the presence of which is essential to elicit an effectiveimmunological response in a human subject to whom a vaccine isadministered. Upon heating, proteins generally denature and quickly losetheir three-dimensional conformation. Denaturation of a small portion ofa vaccine dosage may be enough to compromise the potency of the dosage.Denaturation may occur slowly, as a result of a gradual accumulation oflow-level heat exposure, or quickly, as a result of a peak of moreintense heat exposure. Similar considerations may apply to otherimmunogenic molecules, and complex biologicals, whether natural orsynthetic.

Cumulative time-temperature indicators have often been applied tovaccine vials to monitor historical cumulative heat exposuresexperienced by the vaccine and provide a medical technician, or otheruser, a warning signal that the vaccine has experienced heat exposurethat may have affected its freshness or potency. As noted previouslyherein, a cumulative time-temperature indicator may not respondeffectively to a heat exposure peak of relatively brief duration thatmay also affect freshness or potency.

Thus, a dual-function heat indicator that may signal cumulative ambientheat exposure and peak ambient heat exposure in a single device would beuseful to monitor the heat exposure of heat-sensitive products such as aa vaccine, and for other purposes. Small low-cost indicatorsadditionally would be desirable for application to typical single-dosagevaccine vials that may have a capacity as small as 5 mL, and a cost, inbulk, that may be below U.S. $0.25 per dosage in 2012, in some cases.

The term “dual,” as used herein, refers to at least two and may includemore than two. The term “color” as used herein includes achromaticvisual appearances such as black, gray, and white, as well as chromaticappearances having primary color hues, secondary color hues and/or othercolor hues, such as, without limitation, red, yellow, green, blue,purple, orange, brown and other hues. The terms “color change” and itsgrammatical variants are used to refer to changes in hue, intensity orlightness (or darkness) or other changes in visual appearance.

The time-temperature indicator device described in Prusik et al. '434may be used to signal actual rather than an apparent end of a productlife see e.g. abstract of Prusik et al. '434. The time-temperatureindicator device may employ a diacetylenic monomer-including compositionor another known time-temperature indicator, as a primary indicator oflong term storage of the product. See, e.g., column 4, lines 23-238 ofPrusik et al. '434. As described, the primary indicator is assisted incolor development by a secondary indicator that triggers, for example,melts, at a predetermined temperature range. At temperatures above themelting point, the material becomes mobile and will diffuse through thelayers and add color to the indicator. See, e.g., column 6, lines 26-29of Prusik et al. '434. As the predetermined temperature range isreached, or exceeded, it initiates a color forming change as a result ofthe dissolving of a dye composition. See, e.g., column 6, lines 40-55 ofPrusik et al. '434. Three working examples described in Prusik et al.'434, Examples I-III, also each employ a meltable material and a dyethat apparently dissolves into the meltable material when molten.

According to Prusik et al. '434, the secondary indicia provided by thesecondary indicator of the time-temperature indicator as described maybe made to change rapidly. Such a system could be used, apparently, todetect the thawing of a frozen product, or the melting of a chocolateconfectionary, according to Prusik et al. '434. See, e.g., column 4,lines 50-52.

The diffusion of a meltable material, and dissolution of a dye, althoughapparently occurring rapidly in relation to the thawing of a frozen foodproduct, or the melting of chocolate, may be unduly time-consuming whenthe potential denaturation of a protein needs to be monitored in orderto indicate the probable condition of a vaccine or a comparable product.

Similar considerations may apply to vaccines administered to animals, toother medical products including proteinaceous active components, tocomparable biologicals, and to other similarly heat-sensitive products.

Moreover, the diffusion of a meltable material and the dissolution of adye described in Prusik et al. '434 may require significant ambient heatenergy input, which may delay the appearance of a color change after theonset of an excess temperature exposure peak.

Accordingly, there is a need for a dual-function heat indicator that maymonitor cumulative ambient heat exposure and a peak ambient heatexposure in a single device and provide a quick response to the onset ofa heat exposure peak and a clear signal of possible excess heatexposure. If the peak exposure indicator component of a dual-functionheat indicator responds too slowly to a heat exposure peak, anassociated vaccine, or other heat-sensitive product, may denature andlose its potency, or otherwise deteriorate before exhibiting a colorchange.

A dual-function heat indicator according to some example embodiments ofthe invention may address such needs by employing a meltable solidphysically separating a first reactant from a second reactant whereinthe first reactant is co-reactable with the second reactant to provide acolor change, and the color-changing chemical reaction is induced inresponse to an ambient heat exposure peak. The color-changing chemicalreaction induced by the melting of the meltable solid, as it responds toa heat exposure peak reaching a temperature exceeding the melting pointof the meltable solid, may proceed quickly, providing a prompt colorchange. A temperature above which such a peak exposure indicator willrespond may be predetermined by suitable selection of the component orcomponents of the meltable solid, and the resultant melting point of themeltable solid, and/or the glass transition temperature of the meltablesolid, if the latter is relevant. The meltable solid component, orcomponents, may, in some cases, include either or both of the firstreactant and the second reactant.

A prompt color change, such as a darkening to a distinct dark end point,may help assure that heat exposure peaks that are potentially damagingto an intended host product, for example, a vaccine, will be properlyindicated, for example, by the dark end point, and reduce the risk thata heat exposure peak may have sufficient heat energy to be damaging tothe host product, for example, by denaturing a vaccine's proteins, yetwill fail to trigger the cumulative exposure indicator.

A peak exposure indicator component of a dual-function heat indicatorexample embodiment of the invention may be correlated with, orcalibrated to, a host product that the dual-function heat indicator isintended to monitor by selection of materials to configure the meltingpoint of the peak exposure indicator to not be higher than a thresholdtemperature or temperatures in excess which may be harmful to the hostproduct. An example of a threshold temperature is a temperature in therange of from about 40° C. to about 60° C., which may be suitable formonitoring a vaccine or another host product including an active proteinor other sensitive biological material or the like. Other thresholdtemperatures may also be employed, for example, a threshold temperaturein the range of from about 20° C. to about 70° C., for these or otherapplications.

The cumulative exposure indicator component of a dual-function heatindicator example embodiment of the of the invention may be correlatedwith the heat response characteristics of an intended host product, totrack continuous and/or sporadic lower level exposures to which anassociated host product may be subject. The cumulative exposureindicator may also provide a distinct color change, for example, adarkening to a dark end point, at a suitable predetermined cumulativeheat value, to indicate the probable condition of the host product. Insome example embodiments of the of the invention, the cumulativeexposure indicator may have a dark end point that is similar to the darkend point of the peak exposure indicator, if the latter indicator has adark end point. In some embodiments, the darkening of the cumulativeexposure indicator is achieved by dissolving or etching away a layer ormaterial that obscures a dark background prior to being dissolved oretched away. In such example embodiments, the appearances of the twoindicators may be visually combined in a single area to provide anintegrated signal that may report two partial heat exposures aspotentially representing an adverse heat exposure, in combination.Cumulative exposure indicators, as described herein, are sometimes knownas time-temperature indicators.

The predetermined cumulative heat value may be selected in various ways,as known in the art, for example, to correspond with a probable imminentloss of efficacy or quality of the host product. The cumulative exposureindicator may be configured to provide a desired end point byappropriate selection of a heat-sensing agent to include in thecumulative exposure indicator, as is known in the art, or in anothersuitable manner.

Further, a cumulative exposure indicator employed in an exampleembodiment of the dual-function heat indicator may have a colorless orlightly colored appearance initially, i.e., before activation by heat.In some example embodiments of the invention, the appearance of thecumulative exposure indicator may be transparent or translucent, atleast initially, so that the appearance of the peak exposure indicatormay be viewed or optically read through the cumulative exposureindicator. Thus, the initial appearance of the cumulative exposureindicator may be largely that of the substrate supporting the cumulativeexposure indicator, for example, white. As the cumulative exposureindicator is subjected to thermal exposure, the active surface becomesprogressively darker. However, the cumulative exposure indicator mayretain some transparency, possibly until the end point of the cumulativeexposure indicator is reached.

The term “transparent” is used herein to include “translucent” and torefer to a material which may transmit some or all of the incidentlight, so that bodies, for example, colored surfaces, beyond thematerial are visible, yet which may diffuse, scatter, or block some ofthe incident, light to a limited extent.

The cumulative heat indicator may employ a heat-sensing agent thatprovides the described initially transparent and subsequent darkeningappearances. In some example embodiments of the invention, theheat-sensing agent may be present in particulate form, in admixture withparticles of peak exposure indicator composition. In such exampleembodiments, both the heat-sensing agent and the peak exposure indicatormay contribute to the admixture an initially transparent appearance anda darkening appearance subsequent to heat exposure.

Unless the context indicates otherwise, particulate materials employedin dual-function heat indicator example embodiments of the invention, orin example embodiments of the method, may have various particle sizes,as will be known or apparent to a person of ordinary skill in the art,in light of this disclosure. For example, such particulate materials mayhave an average particle size of not more than about 10 μm, or fromabout 0.5 μm to about 5 μm. Some aspects of the example embodiments ofthe invention employ materials that scatter light and may have differentaverage particle sizes.

The color change exhibited by the peak exposure indicator may beirreversible and may occur after a predetermined ambient heat exposurepeak has occurred. The response of the peak exposure indicator may befurther enhanced, for example, made quicker, by employing particulatefirst and second reactants and dispersing the first and second reactantparticles in the same layer of an example embodiment of thedual-function heat indicator. The meltable solid may partially orcompletely envelop the particles of the first reactant or the particlesof the second reactant or both types of particles, to provide physicalseparation between the two types of particles and prevent them fromreacting prematurely. The particles of the first reactant may beintimately admixed with the particles of the second reactant andphysically separated from by a thin layer of the meltable solid. Waterinsolubility of the first reactant, the second reactant and/or themeltable material may be useful for manufacturing or other purposes.

Further, one or both of the first reactant and the second reactant maybe soluble in the meltable solid. Still further, one of the firstreactant and the second reactant may be dissolved in, or blended with,the solid material. Yet further, the meltable material may be a firstmeltable material and a second meltable material and may partially orcompletely envelop a solution of the first reactant or of the secondreactant in the first meltable material. One or more of these measuresmay be employed to enhance the response of the peak exposure indicator,or for other purposes. For example, such measures may enable the peakexposure indicator to respond quickly after activation by an ambientheat exposure peak, with little, if any, delay for diffusion of anactive material or materials.

In some examples embodiments of dual-function heat indicators accordingto the example embodiment of the invention, the first reactant and thesecond reactant may be solid. The meltable solid may include a thermalsensitizer to modify the melting point of the peak exposure indicator.The meltable solid may include a binder, whether or not the meltablesolid includes a thermal sensitizer.

For use with a host product including an active protein, and for otherpurposes, the peak exposure indicator may have a response temperature inthe range of from about 40° C. to about 60° C. For this purpose, thepeak exposure indicator may be meltable at a temperature near to, or at,its response temperature or at a lower temperature for example up to 2°C. lower. The melting points, or range of melting points, of themeltable ingredients of the peak exposure indicator may be selectedaccordingly.

A first reactant employed in an example embodiment of the dual-functionheat indicator may be or may include a color former. A second reactantmay be or may include a color developer. Optionally, the color former orthe color developer, or both the color former and the color developer,may be colorless initially. The color former may develop color as aresult of reacting with the color developer.

A cumulative exposure indicator employed in an example embodiment of thedual-function heat indicator may include at least one thermallysensitive, polymerizable diacetylenic compound including at least twoconjugated acetylenic groups, for example, a hexadiyn bis(alkylurea)compound.

The color change exhibited by the cumulative exposure indicator may beirreversible and may occur after a predetermined cumulative ambient heatexposure has occurred. The cumulative exposure indicator may employvarious heat-sensing agents, for example, various polymerizablediacetylenic compounds, or other heat-sensing agents, to vary the amountof heat exposure that causes a color change.

Dual-function heat indicator example embodiments of the invention mayexhibit a distinct color change following activation that provides goodcontrast with the appearance of the dual-function heat indicator beforeactivation and a clear, irreversible, signal suggesting that adverseheat exposure may have occurred, for example, a significant darkening ofthe indicator.

The color change may be described in terms of optical density changes.Optical density “OD” as used herein is the log to the base 10 of theinverse of the incident light reflected from a sample. OD may beexpressed by the formulaOD_(λ)=log₁₀(I ₀ /I)where I is the intensity of light at a specified wavelength λ that isreflected by a sample and I₀ is the intensity of the light before itenters the sample, where I is the intensity of light at a specifiedwavelength λ that is reflected by a sample and I₀ is the intensity ofthe light before it enters the sample. Some example embodiments of thedual-function heat indicator may exhibit an optical density differenceof 0.4 OD between the before-activation and the after-activationappearances of the indicator, providing a distinct color change and goodcontrast. Higher optical differences, for example, 0.5 OD or 0.6 OD, orhigher, may also be exhibited. Also, some example embodiments of thedual-function heat indicator may exhibit an optical density differenceof 0.2 OD or 0.3 OD between the before-activation and theafter-activation appearances of the indicator, also providing a distinctcolor change. The color change may be provided by a change in color ofthe cumulative exposure indicator or a change in color of the peakexposure indicator or a combination of changes in color of bothindicators.

An example embodiment of the dual-function heat indicator may include aviewable active area for viewing the cumulative exposure indicatorand/or the peak exposure indicator and may also include a coloredreference area adjacent the active area, which reference area may becolored to show an end point appearance of the active area. The endpoint appearance may be an appearance such as a dark appearance thatindicates a probable condition of an associated host product, forexample, that the host product has lost efficacy or quality and shouldnot be used.

Dual-function heat indicator example embodiments of the invention mayprovide an irreversible, essentially permanent, or non-transitory,record of a historical ambient heat exposure event or events.

One or more other indicators, for example a freeze indicator, may becombined with a dual-function heat indicator example embodiment of theinvention. The freeze indicator may be supported on a common substratewith the dual-function heat indicator. For example, the freeze indicatormay be transparent before activation by exposure to a freezingtemperature and may be supported on the dual-function heat indicator,and the dual-function heat indicator may be viewable through the freezeindicator. Such a construction may provide a simple, compact indicatorthat may integrate responses to three different environmental inputs:freeze, cumulative heat, and a heat peak, into a single signal, for easycomprehension. Suitable freeze indicators and ways of supporting afreeze indicator on a substrate with one or more other ambient conditionindicators are described in U.S. Pat. No. 7,490,575 to Taylor et al.Other suitable freeze indicators are described in U.S. Pat. No.7,891,310 to Taylor et al. and U.S. Pat. No. 8,122,844 to Smith et al.

A substrate employed in an example embodiment of the dual-function heatindicator may be configured to be conformable with a host product, orpackaging for a host product, for example a vaccine vial containing avaccine. The substrate may be flat to conform with a flat surface of thehost product (or to a package containing the host product).Alternatively, the substrate may be curved in one dimension, or in twodimensions, to conform with a curved surface of the host product (or ofa package containing the host product), for example, the curved surfaceof a cylindrical vaccine vial. Also, a substrate may enable thedual-function heat indicator to be attachable to a host product, forexample, by bearing a pressure-sensitive adhesive layer. Adhesiveattachment is one example of different ways in which the dual-functionheat indicator may be associated with a host product to monitor the hostproduct for heat exposure. Possible different ways of attachmentinclude, for example, adhering, tying, looping, and stapling, to thehost product directly, or to a package containing the host product, orto a package, carton, box or other container containing a number of hostproduct items. Further, a dual-function heat indicator embodied in alabel, or tag, may be inserted in a host product package, carton, orother container for one or more host product items.

Some example embodiments of the dual-function heat indicator may employa thermal paper, i.e., a paper bearing a thermal coating, the paperfunctioning as a substrate and the thermal coating functioning as a peakexposure indicator. The characteristics of the thermal coating may beselected, or modified, to provide a thermal paper having peak exposureindicator characteristics rendering the thermal paper suitable for usein an example embodiment of the dual-function heat indicator, incooperation with a cumulative exposure indicator.

An example of a thermal paper that may be employed is a light weight,well-formed, smooth paper having a thermally responsive surfacetreatment or coating including color-forming reactants. Some examples ofsuitable color-forming reactants are a leuco dye precursor as a firstreactant, and a developer for the leuco dye as a second reactant. Theleuco dye precursor and developer may be solid particulates. Thecolor-forming reactants may be incorporated in a matrix that constitutesa meltable solid. The resultant matrix may be applied to a paper sheet,or continuous paper web, or another suitable substrate. For example, thematrix may be dispersed in a liquid medium and the resultant liquiddispersion may be coated on the substrate and dried. Drying may beconducted at a temperature of at least 2° C. below the melting point ofthe matrix material to avoid melting the matrix material, employingforced convection, low humidity, for example, a relative humidity belowabout 50% or below about 40%, and/or an extended drying time. Uponmelting, the matrix may enable the leuco dye precursor and developer tomerge and develop color.

The thermally responsive coating may also include a thermal sensitizer.The thermal sensitizer may have a relatively low melting point such thatthe melting point of the thermally responsive coating does not exceed adesired threshold temperature for the host product. Also, the thermalsensitizer may be a solvent for one, or both, of the color-formingreactants so that after the thermal sensitizer melts, following exposureto heat, one or both of the color-forming reactants dissolve in thethermal sensitizer. The melting point of the resultant solution of thesensitizer and reactant may be below the melting point of thesensitizer, reducing the response temperature of the peak exposureindicator, in some cases.

Optional additional ingredients of a thermal paper employed in thepractice of the example embodiment of the invention include: stabilizersto enhance image durability, referring to the color image generated byheat exposure; fillers or pigments to extend and/or opacify the coating;binders to hold the coating components together and possibly toseparate, or help separate, the reactive components; lubricants to helpthe paper move steadily and smoothly on a printing press or othermanufacturing equipment; dispersants; defoamers; viscosity controllers;and/or antistatic agents. One or more of these optional additionalingredients may be employed according to the requirements of aparticular application. A thin clear coat, for example, a coat of apolyurethane or another suitable synthetic polymer, may be applied overthe thermal coating to add durability and improve writability, ifdesired.

In one exemplary method of manufacturing a suitable thermal paper, aleuco dye precursor or other color-forming reactant may be mixed with athermal sensitizer and milled to a suitable particle size. Optionally,the resultant particles may be encapsulated with a meltable capsulematerial having a suitable melting point, for example, a poly-condensatepolymer such as a cross-linked amino-formaldehyde resin, yieldingcapsules or microcapsules of the color-forming reactant. Separately, acolor developer may also be mixed with the thermal sensitizer and may beadded to the other coating ingredients, also as a solid at roomtemperature. The melting points of the thermal sensitizer(s) and themeltable capsule material may be selected according to the intendedresponse temperature of the peak exposure indicator. If greaterseparation of the color reactants is desired, the color developer mayalso be encapsulated in the thermal sensitizer. The thermal sensitizermaterial employed for the color developer, if any, may be the same asthat employed for the color-forming reactant, or may be a different, butcompatible, thermal sensitizer material.

On exposure to temperatures above a threshold, the capsule material maysoften and become permeable. If the thermal sensitizer also hassoftened, or melted, the color-forming reactants may mix and react toprovide a color change. In such example embodiments of the invention,the thermal sensitizer and/or the capsule material may provide aphysical separation between the color-forming reactant and the colordeveloper to prevent contact between the two color reactants. Physicalseparation may usually be maintained so long as the thermal paper is notexposed to temperatures above the threshold temperature, for example,during manufacture of the thermal paper, manufacture of thedual-function heat indicator, storage, shipping, display, and/or use.

Dual-function heat indicator example embodiments of the invention may bemanufactured in various ways. One example of a suitable manufacturingmethod includes preparing a peak exposure indicator composition forincorporation in the dual-function heat indicator. The peak exposureindicator composition may be prepared by mixing a leuco dye precursorthat is solid at room temperature with a thermal sensitizer that is alsosolid at room temperature. The mixed ingredients may be milled and thenencapsulated with a suitable meltable capsule material, for example, apoly-condensate polymer such as a cross linked amino-formaldehyde resin.A leuco dye developer may be included in the peak exposure indicatorcomposition by mixing the leuco dye developer with thermal sensitizermaterial, both materials optionally being solid particulates at roomtemperature, and adding the developer mixture to the peak exposureindicator composition.

Referring now to FIGS. 1 and 2 of the accompanying drawings, the twoexample embodiments of the dual-function heat indicators shown,referenced 10 in FIGS. 1 and 2, may monitor cumulative ambient heatexposure and a peak ambient heat exposure in a single device. Multipledual-function heat indicators 10 may be embodied as labels and may besupported on a liner 12 for production in quantity. Various otherconfigurations of dual-function heat indicator 10 are possible. FIG. 1shows a section of liner 12 on which a number of dual-function heatindicators 10 may be arranged in series, for mass production of thedual-function heat indicators, using print industry technology, orpackaging industry technology, or the like. Such label exampleembodiments may be produced at low cost in self-adhesive configurationsand may be suitable for attachment to the outer surface of amass-produced host product, or to packaging or a container for the hostproduct.

FIG. 2 is a cross-sectional view taken along imaginary line 2-2 in FIG.1 which demonstrates that dual-function heat indicator 10 may comprise asubstrate 14, bearing an adhesive layer 16, which may be pressuresensitive, and which removably adheres substrate 14 to liner 12, so thatdual-function heat indicator may be applied to a host product or apackage or carton. For this purpose, liner 12 may be a release linerthat is coated with a suitable low surface energy material to facilitateremoval of adhesive-coated substrate 14. Substrate 14 has a centralactive region, which bears a color-changing composition 18.Color-changing composition 18 displays an active surface 20 upwardlywith respect to substrate 14 for optical reading externally ofdual-function heat indicator 10. Active surface 20 displays the addedresponses of the peak and cumulative components of color changingcomposition 18. A transparent or opaque reference material 22 may beconfigured in a ring extending around color-changing composition 18, orin another suitable configuration (not shown) alongside or nearcolor-changing composition 18. Reference material 22 displays a staticsurface 24 upwardly with respect to substrate 14 for optical readingexternally of dual-function heat indicator 10. The appearances of activesurface 20 and static surface 24 may be optically read by a human vieweror by a suitable image processing device, for example, a camera.

A transparent film 26 may overlie color-changing composition 18 andreference material 22 to provide protection from physical abrasion orabuse. Transparent film 26 may be secured to color-changing composition18 and reference material 22 by a layer of adhesive (not shown), or inanother suitable manner. Transparent film 26 may bear printed indiciaproviding identifying or instructional, or other information regardingthe dual-function heat indicator and/or an associated host product.Transparent film 26 may be colored to filter out incident ambient lightat wavelengths that may adversely affect color-changing composition 18and may be substantially inert. For example, transparent film 26 may becolored orange or red. Optionally, transparent film 26 may include anultraviolet filter material to filter, or block incident ultravioletradiation. Transparent film 26 may be sufficiently transparent thatactive surface 20 and static surface 24 may be viewed and that thecolors, or at least the optical densities at active surface 20 andstatic surface 24, and changes in the color or optical density at activesurface 20 and static surface 24, may be viewed and/or optically read.

Dual-function heat indicator 10, color-changing composition 18, andreference material 22 may have any desired shape. The shapes, consideredindependently, may be circular, square, rectangular, triangular,hexagonal, polygonal, elongated, circular, oval, elliptical, strip-like,another regular shape, an irregular shape, a shape representing arecognizable image such as a check mark, or another suitable shape. Asshown in FIG. 1, by way of example, dual-function heat indicator 10 iscircular, reference material 22 occupies a smaller circle, andcolor-changing composition 18 is configured as a square within thecircle of reference material 22.

In the transverse dimension shown in FIG. 2, dual-function heatindicator 10 has a layered structure. The shapes and relative dimensionsof the various layers may be varied significantly. One exampleembodiment of dual-function heat indicator 10 has thin, laminar layersto provide a low-profile device that may have a compact configurationand may be applied to small host products such as vaccine vials and thelike.

The size of a dual-function heat indicator such as dual-function heatindicator 10 may vary according to the intended application, or forother purposes. Some example embodiments of such a dual-function heatindicator may have a largest transverse dimension, which may be adimension in the plane of FIG. 1A, in the range of from about 5 mm toabout 30 mm, for example, from about 10 mm to about 15 mm. In such anembodiment, active surface 20 may have a largest transverse dimension offrom about 1 mm to about 10 mm, for example, from about 2 mm to about 6mm.

Color-changing composition 18 may include a heat-sensing agent thatfunctions as a cumulative heat indicator and a peak exposure indicatorcomposition that functions as a peak exposure indicator. Suitableheat-sensing agents and peak exposure indicator compositions aredescribed elsewhere herein. Thus, color-changing composition 18 maychange color in response to cumulative heat exposure and may also changecolor in response to peak heat exposure. In this way, the cumulativeexposure indicator and the peak exposure indicator may be integratedinto a single layer of dual-function heat indicator 10.

The heat-sensing agent and the peak exposure indicator composition maybe configured on substrate 14 so that the appearances of theirindividual color responses at active surface 20 are mixed additively,i.e. so that any darkening of the cumulative exposure indicator adds toany darkening of the peak exposure indicator to provide a still darkerappearance at active surface 20. In terms of optical density, theindividual optical densities of the individual appearances areconsidered. The heat-sensing agent and the peak exposure indicatorcomposition may be configured by admixing or blending particulates invarious ways. For example, particles of the heat-sensing agent andparticles of the peak exposure indicator composition may be dispersed ina common liquid vehicle, the resultant dispersion may be dispersed onsubstrate 14, and the liquid vehicle then may be evaporated, or theparticulates may be applied to substrate 14 in a radiation-curablecoating, which may then be cured with the appropriate radiation.

Reference material 22 may help a viewer or viewing device judge thestate of color-changing composition 18 by having an appearance similarto the appearance color-changing composition 18 which will develop aftera predetermined cumulative heat exposure indicative of an end point.

In another example embodiment as demonstrated in FIG. 1A, dual-functionheat indicator 10 may have a substrate 14 with a substrate printablemargin 14A on which printed indicia 28 may be printed. FIG. 2A shows across sectional view taken along imaginary line 2A-2A in FIG. 1A. FIG.2A demonstrates that the substrate printable margin 14A surrounds/liesin an outer ring fashion around color changing composition 18 andreference material 22. Otherwise, dual-function heat indicator 10 shownin FIGS. 1A and 2A may be very similar to that in FIGS. 1 and 2, in thatthe dual-function heat indicator in FIGS. 1A and 2A may also include aliner 12, a substrate 14, an adhesive layer 16, an active surface 20, areference material 22, a static surface 24, and optionally, atransparent film 26. As such, these components are given the samereference numerals in FIGS. 1A and 2A and are not described furtherhere.

Referring to FIG. 3, the dual-function heat indicator shown, referenced30 in FIG. 3, is generally similar to dual-function heat indicator 10,with the difference that a cumulative exposure indicator and a peakexposure indicator are configured in separate, individual layers ratherthan being integrated into a single layer of the device, as indual-function heat indicator 10. The cumulative exposure indicator andpeak exposure indicator are prepared and printed separately. In planview, dual-function heat indicator 30 is similar to dual-function heatindicator 10 so that no additional plan view of dual-function heatindicator 30 is shown.

Like dual-function heat indicator 10, dual-function heat indicator 30may include a liner 12, a substrate 14, an adhesive layer 16, an activesurface 20, a reference material 22, a static surface 24, optionally, atransparent film 26 and, optionally, printed indicia 28 (not shown inthe cross-section). Accordingly, these components are given the samereference numerals in FIG. 3 and are not described further here.

Dual-function heat indicator 30 further includes a peak exposureindicator 32 supported on a central region of substrate 14, and acumulative exposure indicator 34 overlying peak exposure indicator 32.Cumulative exposure indicator 34 may be initially transparent prior toheat exposure so that the appearance of peak exposure indicator 32 isoptically readable or viewable through cumulative exposure indicator 34.Thus, dual-function heat indicator 30 combines the appearances of thecumulative exposure indicator and the peak exposure indicator. With thisconfiguration, an end point may be individually indicated by thecumulative exposure indicator, by the peak exposure indicator, or by acombination of a partial exposure of each indicator.

In one example embodiment of the use of dual-function heat indicator 30,in response to a brief exposure to a temperature above a predeterminedpeak temperature, cumulative exposure indicator 34 remains essentiallytransparent and lighter in color than reference surface 22. Meanwhile,active surface 20 of combined cumulative explosive indicator 34 and peakexposure indicator 32 darkens rapidly reaching the end point ofdual-function heat indicator 30. Darkening occurs as a result of themelting of a wax matrix, or other meltable solid, and the chemicalreaction of the dye precursor with the dye developer, or of othercolor-changing reactants.

Dual-function heat indicator 30 may provide manufacturing or productbenefits arising from the separation of the heat-sensing agent employedin cumulative exposure indicator 34 into one layer, if a heat-sensingagent is employed, while the color-forming reactants employed in peakexposure indicator 32 are in another layer.

In a modified example embodiment of dual-function heat indicator 30 (notshown), peak exposure indicator 32 is disposed on top of cumulativeexposure indicator 34. In this case, peak exposure indicator 32 may betransparent to permit the appearance of cumulative exposure indicator 34to be viewed, or read optically, at active surface 20, whereascumulative exposure indicator 34 may now be either transparent oropaque. Active surface 20 displays the added responses of the peak andcumulative components.

Referring to FIG. 4, the dual-function heat indicator shown, referenced40 in FIG. 4, is also generally similar to dual-function heat indicator10. Like dual-function heat indicator 30 in the FIG. 3 exampleembodiment, dual-function heat indicator 40 differs from dual-functionheat indicator 10 by having a cumulative exposure indicator and a peakexposure indicator that are configured in separate individual layers.However, in contrast to the FIG. 3 example, in dual-function heatindicator 40, the peak exposure indicator is integrated into a singlelayer with a substrate.

Once again, dual-function heat indicator 40 has a similar plan view tothat of dual-function heat indicator 10 so that no additional plan viewof dual-function heat indicator 40 is shown.

Like dual-function heat indicator 10, dual-function heat indicator 40may include a liner 12, an adhesive layer 16, an active surface 20, areference material 22, a static surface 24, optionally, a transparentfilm 26 and, optionally, printed indicia 28 (not shown in thecross-section). Accordingly, these components are given the samereference numerals in FIG. 4 and are not described further here.

Dual-function heat indicator 40 further includes an active substrate 42and a cumulative exposure indicator 44 supported on active substrate 42.Active substrate 42 provides substrate functionality similar to that ofsubstrate 14 of dual-function heat indicator 10 and may be fabricatedfrom similar substrate materials, for example, paper or syntheticpolymer material. In addition, active substrate 42 includes a peakexposure indicator. The peak exposure indicator may be provided as adeposit of a peak exposure indicator composition, on the upper surfaceof active substrate 42. This deposit or coating is not referencedseparately in FIG. 4. As described in more detail elsewhere herein, thepeak exposure indicator composition may include a first reactant and asecond reactant. The second reactant may co-react chemically with thefirst reactant to provide a color change and the peak exposure indicatorcomposition may be meltable to induce the color change. In this exampleembodiment of the dual-function heat indicator, the peak exposureindicator embodied in active substrate 42 extends beneath referencematerial 22. Accordingly, reference material 22 may be opaque, and maylack transparency, so that the upper surface of active substrate 42 isnot viewable through reference material 22, as this view could beconfusing when active substrate 42 darkens as a result of a heatexposure peak.

Cumulative exposure indicator 44 may be similar to cumulative exposureindicator 34 in the FIG. 3 example embodiment of a dual-function heatindicator already described. Thus, cumulative exposure indicator 44 maybe transparent initially and the appearance of the peak exposureindicator applied to the upper surface of active substrate 42 may beoptically readable or viewable through cumulative exposure indicator 44.Like dual-function heat indicator 30, dual-function heat indicator 40combines the appearances of the cumulative exposure indicator and thepeak exposure indicator. With the configuration of dual-function heatindicator 40 shown in FIG. 4, an end point may also be indicatedindividually by the cumulative exposure indicator or the peak exposureindicator, or by a combination of a partial exposure of each indicator.

Dual-function heat indicator 40 illustrates an example embodiment of theinvention wherein active substrate 42 may be self-supporting prior toassembly into dual-function heat indicator 40 and may be supplied to apoint of manufacture from bulk stock such as a sheet, strip or acontinuous web of material. This capability may assist the manufacturingprocess. Also, deposition of the peak exposure indicator composition onsuitable substrate material may be performed prior to manufacture ofdual-function heat indicator 40, which may simplify the manufacturingprocess.

In a modified example embodiment of dual-function heat indicator 40 (notshown), active substrate 42 is disposed on top of cumulative exposureindicator 44. In this case, active substrate 42 may be transparent topermit the appearance of cumulative exposure indicator 44 to be viewed,or read optically, at active surface 20, whereas cumulative exposureindicator 44 may be either transparent or opaque. In this modifiedexample embodiment, an inactive substrate layer, like substrate 14 shownin FIGS. 2 and 3, may also be employed between adhesive layer 16 andcumulative exposure indicator 44, as shown in FIG. 4, to providesupport.

Referring to FIG. 5, the dual-function heat indicator shown, referenced50 in FIG. 5, is also generally similar to dual-function heat indicator10. Like dual-function heat indicator 40 in the FIG. 4 exampleembodiment, dual-function heat indicator 50 differs from dual-functionheat indicator 10 by having a cumulative exposure indicator and a peakexposure indicator that are configured in separate individual layers.Cumulative exposure indicator 44 and peak exposure indicator 52 areconfigured in separate layers. However, in contrast to the FIG. 4example embodiment, in dual-function heat indicator 50, the peakexposure indicator may include three layers, namely, activator 54, colorchanging composition 56, and barrier 58. Activator 54 may be a meltablesolid which when liquid is a solvent for one or both co-reactants or itmay be a reactant. Activators were screened and it was found thatmeltable activators may be chosen with different effective temperaturesso that thermal coatings with normally high thermal responsetemperatures and temperate dependent color development may be used for afamily of peak indicators with a lower activation temperature suitablefor the dual indicators in this disclosure. A few activators include,but are not limited to, heptadecanol, 4-methoxyphenol, pentadecanol,2,4-di-tert-butyl phenol or benzophenone. Various treatments ofoff-the-shelf commercial or pre-manufactured papers may be used to lowertheir activation temperature. Color changing composition 56 may includea first reactant and a second reactant, which may co-react chemically toprovide a color change. Color changing composition 56 may be layer orcoating on substrate 14. Barrier 58 may be a thin clear coating on thesurface of color changing composition 56 to prevent direct contact ofactivator 54 in the solid state with color changing composition 56 andto provide durability.

Like dual-function heat indicator 10, dual-function heat indicator 50may include a liner 12, a substrate 14, an adhesive layer 16, an activesurface 20, a reference material 22, a static surface 24, optionally, atransparent film 26 and, optionally, printed indicia (not shown) asdemonstrated in FIG. 5. Accordingly, these components are given the samereference numerals in FIG. 4 and are not described further here.

In a further example embodiment of dual-function heat indicator 50,dual-function heat indicator 50 may omit cumulative exposure indicator44 so that peak exposure indicator 52 including activator 54, colorchanging composition 56, and barrier 58 is used as a standalone peakindicator.

Referring to FIG. 6, the dual-function heat indicator shown, referenced60 in FIG. 6, is also generally similar to dual-function heat indicator10. Like dual-function heat indicator 40 in the FIG. 4 exampleembodiment, dual-function heat indicator 60 differs from dual-functionheat indicator 10 by having a cumulative exposure indicator and a peakexposure indicator that are configured in separate individual layers.Cumulative exposure indicator 44 and peak exposure indicator 62 areconfigured in separate layers. However, in contrast to the FIG. 4example embodiment, in dual-function heat indicator 60, the peakexposure indicator may include three layers, namely, reactant B 64,reactant A 66, and meltable barrier 68. Reactant B 64 may be a layerincluding either of the co-reactants described previously, or it may bea coating on substrate 14. Further reactant B 64 may be a mixtureincluding binders. Reactant A 66 may be a layer including thecomplementary color generating co-reactant for reactant B 64. Furtherreactant A 66 may be a mixture including binders. Meltable barrier 68may be a continuous layer of a meltable solid separating reactant A 66and reactant B 64. Neither reactant A 66 nor reactant B 64 is able topass through barrier 68 while it is a solid. Once meltable barrier 68melts into liquid form reactant A 66 and reactant B 64 may co-reactchemically to provide a color change.

Like dual-function heat indicator 10, dual-function heat indicator 60may include a liner 12, a substrate 14, an adhesive layer 16, an activesurface 20, a reference material 22, a static surface 24, optionally, atransparent film 26 and, optionally, printed indicia (not shown) asdemonstrated in FIG. 6. Accordingly, these components are given the samereference numerals in FIG. 4 and are not described further here.

In a further example embodiment of dual-function heat indicator 60,dual-function heat indicator 60 may omit cumulative exposure indicator44 so that peak exposure indicator 62 including reactant B 64, reactantA 66, and meltable barrier 68 is used as a standalone peak indicator.

Referring to FIG. 7, the dual-function heat indicator shown, referenced70 in FIG. 7, is also generally similar to dual-function heat indicator10. Like dual-function heat indicator 40 in the FIG. 4 exampleembodiment, dual-function heat indicator 70 differs from dual-functionheat indicator 10 by having a cumulative exposure indicator and a peakexposure indicator that are configured in separate individual layers.Cumulative exposure indicator 44 and peak exposure indicator 72 areconfigured in separate layers. However, in contrast to the FIG. 4example embodiment, in dual-function heat indicator 70, the peakexposure indicator may include two layers, namely, color layer 74 andopaque layer 76. Color layer 74 may have an intense color such as blackor red and may be configured as a layer on top of substrate 14. Opaquelayer 76 may be a meltable solid applied as a coating or ink onto colorlayer 74 or may be small particles that scatter light rendering thelayer opaque. Upon melting opaque layer 76 becomes transparent and colorlayer 74 may be seen through it. Opaque layer 76 may be a wax.

Like dual-function heat indicator 10, dual-function heat indicator 70may include a liner 12, a substrate 14, an adhesive layer 16, an activesurface 20, a reference material 22, a static surface 24, optionally, atransparent film 26 and, optionally, printed indicia (not shown) asdemonstrated in FIG. 7. Accordingly, these components are given the samereference numerals in FIG. 4 and are not described further here.

In yet a further example embodiment, dual-function heat indicator 80 formonitoring cumulative ambient heat exposure and peak ambient heatexposure includes a substrate 14, a cumulative exposure indicatorsupported by the substrate in one viewable layer 44, and a peak exposureindicator 82 which may include meltable particulate colored material 84supported by substrate 14 in another viewable layer as shown in FIG. 8.Dual-function heat indicator 80 may further include a liner 12, anadhesive layer 16, an active surface 20, a reference material 22, astatic surface 24, optionally, a transparent film 26 and, optionally,printed indicia (not shown). The cumulative exposure indicator 44 may becolor-changeable in response to cumulative ambient heat exposure, andthe peak exposure indicator 82 may include a meltable particulatecolored material 84. In this example embodiment, the meltableparticulate colored material 84 may have an average particle sizeimbuing the meltable particulate colored material 84 with a light color,the light color being attributable to scattering of visible light by themeltable particulate colored material 84. Optionally, the meltableparticulate colored material 84 may include a meltable solid and a dyedissolved in the meltable solid.

Melting of the meltable particulate colored material 84 may cause themeltable particulate colored material 84 to darken in color and thedarkening may be irreversible so that the peak exposure indicator 82provides an irreversible signal. The darkening may be induced by anambient heat exposure peak reaching a temperature exceeding the meltingpoint of the meltable particulate colored material 84. Thus,dual-function heat indicator 80 may indicate cumulative ambient heatexposure or peak ambient heat exposure by changing color.

Prior to activation, the meltable particulate colored material 84 maygive peak exposure indicator 82 a light color due to light scattering.When the meltable particulate colored material 84 softens or melts inresponse to ambient heat exposure peak, the small colored particles maycoalesce, merge and/or fuse, to provide one or more larger coalescedmasses or agglomerations that may exhibit the inherent color of thecolored material. The inherent color may be a dark, or strongly coloredappearance that the colored material exhibits in bulk, for example, in acontinuous film. The inherent color may also be opaque. The meltableparticulate colored material 84 may obscure any background behind themeltable particulate colored material 84 so that the background may notbe viewed accurately through the meltable particulate colored material84. Employing a dye or other colorant, or by using a meltable solidhaving an inherent color, dark or strong colors, such as an intense red,or black, may be displayed so that the peak exposure indicator 82exhibits good contrast between its appearances before and afteractivation, such as is described elsewhere herein.

The meltable particulate colored material 84 may provide a color changewithout significant migration of the meltable particulate coloredmaterial 84 or a meltable component thereof. For example, the meltableparticulate colored material 84 may remain immobile within one layer ofdual-function heat indicator 80. However, some small-scale migration ofthe meltable particulate colored material 84 may occur as the particlesmelt and coalesce, or merge, with adjacent particles, possibly forming afilm, or coherent area or areas of colored material, or simply to formlarger particles that are visible. Further, the meltable particulatecolored material 84 may provide a color change non-chemically, withoutreacting with a color developer or otherwise entering into a chemicalreaction.

Various meltable solids may be employed as a component of the meltableparticulate colored material 84, as will be known or apparent to aperson of ordinary skill in the art, in light of this disclosure, orwill become known or apparent in the future. Some examples of suitablemeltable solids include alkanes, alkyl esters, undecane, dodecane,tridecane, tetradecane, pentadecane, hexadecane, heptadecane,octadecane, nonadecane, eicosane, heneicosane, hexanoic acid, hexadecaneand ethyl lactate, waxes, wax materials such as a paraffin wax, amicrocrystalline wax, carnauba wax, beeswax, Chinese wax, shellac wax,spermaceti, tallow, palm wax, soy wax, lanolin, wool grease, a waxypolymer, a waxy copolymer, a polyolefin, polyethylene, polypropylene, anethylene-vinyl acetate copolymer, an ethylene-acrylic acid copolymer andmixtures of any two or more of the foregoing wax materials. Some othermaterials useful as meltable solids in this aspect of the exampleembodiment of the invention include the thermal sensitizers describedherein. A meltable solid having a melting point corresponding with adesired threshold temperature for the peak exposure indicator may beselected. The meltable particulate colored material 84 may be formulatedwithout employing a solid side-chain crystallizable polymer, if desired.Some meltable solids may be selected according to how their glasstransition temperatures relate to the desired threshold temperature, ifappropriate. Thus, the threshold temperature of the peak exposureindicator may be varied by suitable selection of the meltable solid,with due allowance for the effect of the dye upon the melting point ofthe meltable solid, if any.

FIG. 9 illustrates another embodiment of a dual-function heat indicator90 in plan view. Indicator 90 includes a cumulative indicator 91 and apeak threshold indicator 92. Cumulative indicator 91 may include aheat-sensitive ink 91A, such as a diacetylene-based ink, that changesappearance with exposure to heat. Cumulative indicator 91 may alsoinclude a reference surface 91B positioned adjacent to heat-sensitiveink 91A so as to provide an indication—as the appearance ofheat-sensitive ink 91A changes—of when indicator 90 has been exposed totoo much heat. In some embodiments reference surface 91B is dark, andheat-sensitive ink 91A darkens with exposure to heat to the color or hueof reference surface 91B. FIG. 9 illustrates heat-sensitive ink 91A andreference surface 91B as occupying the same layer within cumulativeindicator 91; however, in some embodiments, the separate componentsoccupy different layers with reference surface 91B positioned above orbelow heat sensitive ink 91A. A transparent layer 93, such as a PETfilm, may cover and protect both heat-sensitive ink 91A and referencesurface 91B. In some embodiments, transparent layer 93 may be appliedover heat-sensitive ink 91A, and reference surface 91B may be appliedover transparent layer 93.

Peak threshold indicator 92 includes a meltable solid 92A and asubstrate 92B. Substrate 92B exhibits a particular color orappearance—whether from the substrate's inherent color or an appliedcoating or ink—that is at least partially obscured by thelight-scattering effect of meltable solid 92A. An optional ink layer orcolor coating 92C may be included on top of substrate 92B. Whenindicator 90 is exposed to a temperature above a certain threshold,meltable solid 92A at least partially melts, which allows the underlyingsubstrate 92B to be visible through the various intervening layers. Alaminating adhesive may be used to secure meltable solid 92A betweencumulative indicator 91 and substrate 92B. Additionally, the undersideof substrate 92B may be coated with an adhesive 95, such as apressure-sensitive adhesive, covered by a release liner 96 for easyapplication.

Cumulative indicator 91 and peak threshold indicator 92 may befunctionally separate. The central active region of dual indicator 90,as viewed from above, appears visually white or lightly colored at thetime of manufacture. Reference surface 91B may be a reference ringprinted around the outside in a blue color that has been carefullymatched to the target end point of cumulative indicator 91, e.g., 30days at 37° C. In some embodiments, the target end point is 30 days at atemperature of at least 5° C., at least 10° C., at least 15° C., atleast 20, at least 25° C., or at least 35° C. In some embodiments, thetarget end point is a particular temperature exposure for at least 5days, at least 10 days, at least 15 days, at least 20 days, or at least25 days. In some embodiments, the target end point is a duration andtemperature between about 5 days at 5° C. and about 30 days at 40° C.

Cumulative indicator 91 may be manufactured from a diacetylene-based inkthat—independently of peak threshold indicator 92—undergoes aprogressive, light-to-dark color change at a temperature-dependent rate.Since the diacetylene ink layer may be somewhat transparent, itsappearance will depend to some extent upon the color of the layersbeneath it. As long as the threshold indicator remains un-activated,there will be a consistent white or lightly colored background uponwhich the diacetylene color change from white to increasingly darkershades of blue will be viewed. The active region and reference ring maymatch or substantially match when the cumulative end pointtime-temperature conditions are reached, provided the thresholdtemperature has not been exceeded. After the cumulative end pointtime-temperature conditions are reached, the cumulative indicator willcontinue to darken.

Threshold indicator 92 has a substrate layer that may be eitherinherently dark, e.g. a grey or black dyed film, or is printed with adark ink, e.g. grey, blue, or black. The active portion of thresholdindicator 92 may be a coating that contains particulate meltable solid92A. In some embodiments, meltable solid 92A is held together with asmall amount of binder such that there are air gaps between particles.The particulate nature of the coating causes it to scatter light, givingit an opaque white appearance. If the threshold temperature is exceededat any point, the melting of the solid causes the particles to coalesceand the air voids to be squeezed out so that this layer becomestransparent or translucent. The dark background that was previouslyobscured then becomes visible through the now transparent meltable solidlayer 92A as well as the semi-transparent diacetylene ink layer 91A, andthe active center region of dual indicator 90 appears to darken to adark gray or black. This opaque white-to-dark transition is a relativelyquick process, occurring over a period of minutes if the temperatureremains above the threshold value. Since the color of the reference ringis matched to the cumulative indicator, as explained above, the responsecolor of the peak threshold indicator may be such that it is darker thanthe reference ring.

Dual indicator 90 may be fabricated by supplying substrate 92B that mayalready exhibit a desirable color or is painted or coated with amaterial, such as dark ink, to obtain the desired color. Laminatingadhesive 94 is applied to substrate 92B, and meltable solid 92A isapplied to laminating adhesive 94. Over meltable solid 92A may beapplied heat-sensitive ink 91A, which may include reference surface 91Bplaced adjacent to heat-sensitive ink 91A. Transparent film 93 may beapplied over heat-sensitive ink 91A. In some embodiments, a barrierlayer is included between heat sensitive ink 91A and meltable solid 92A.To the back or underside of substrate 92B may be applied adhesive 95 aswell as release liner 96 to be removed upon application of indicator 90on a suitable surface.

In some embodiments, the various layers comprising peak thresholdindicator 92 are assembled or fabricated, and the various layerscomprising cumulative indicator 91 are assembled or fabricated. The twoindicators may then be assembled together to form dual indicator 90.

In some embodiments, the response time of peak threshold indicator 90 isless than 30 minutes, less than 20 minutes, less than 10 minutes, orless than 5 minutes. In some embodiments, the threshold temperature isat least 10° C., at least 15° C., at least 20° C., at least 30° C., atleast 40° C., or at least 50° C.

FIG. 10 illustrates yet another embodiment of a dual-function heatindicator 100 in plan view. Indicator 100 includes a peak thresholdindicator 101 and a cumulative indicator 102. Threshold indicator 101and cumulative indicator 102 may be functionally separate. The centralactive region of the dual indicator 100 may appear white or lightlycolored at the time of manufacture. A reference ring 104 may be printedin an intermediate shade of grey (or some other color, such as blue)that has been carefully matched to the target end point of cumulativeindicator 102 as it appears viewed through the meltable solid coating101A of threshold indicator 101. Reference ring 104 may be printed inany number of locations.

A transparent layer 105, such as a PET film, may cover and protect bothmeltable solid 101A and reference ring 104. In some embodiments,transparent layer 105 may be applied over meltable solid 101A, andreference ring 104 may be applied over transparent layer 105.

Peak threshold indicator 101 may include a meltable semi-opaque dyed orpigmented coating 101A that may be printed on or under a transparentfilm. The coating 101A contains a particulate meltable solid that may beheld together with a small amount of binder. This may produce air gapsbetween particles causing coating 101A to scatter light, giving it anappearance that may be an opaque white appearance, irrespective of thepresence of the dye or pigment. However, when the threshold or meltingtemperature of the meltable solid is reached coating 101A may develop acolor. Where the particles are dyed, the color develops simply as aresult of the absence of light scattering allowing the inherent color ofthe dye to become visible. In the case of a pigmented coating, where thepigment and meltable solid are both initially present in solid form, thecolor may develop as a result of the pigment being dissolved by themelted solid as well as the absence of light scattering, and the peakthreshold response may be deliberately delayed by the need fordissolution to occur. In either case, the shade of color that developsas a result of a peak threshold temperature being reached may be darkerthan printed reference ring 104.

Cumulative indicator 102 may include an active reactant layer 102A, suchas a layer of aluminum, located above and obscuring a substrate 102Dthat may be printed with a color, such as a color matching referencering 104. For example, an optional ink layer or color coating 102E maybe included on top of substrate 102D. Cumulative indicator 102 furtherincludes a passive reactant layer 102B that may be a pressure-sensitivelaminating adhesive containing acid etchant. The acid may be one that isselected to react with the aluminum layer at a desired time- andtemperature-dependent rate. The aluminum layer 102A becomes thinner andeventually is removed, allowing the printed color of substrate 102D tobecome visible. Cumulative indicator 102 operates independently of peakthreshold indicator 101. A barrier coating 103, e.g., an impermeablebarrier, may be included between threshold indicator 101 and cumulativeindicator 102 so as to prevent the etchant of cumulative indicator 102from adversely affecting the various components of threshold indicator101. If barrier coating 103 is printed between laminating adhesive 102Band meltable solid 101A, the purpose can be to protect meltable solid101A from the effects of the acid etchant and thereby prevent prematuretriggering of peak threshold indicator 101. An optional barrier coating102C, e.g., a semipermeable barrier or a barrier affected bytemperature, may be printed between laminating adhesive 102B andaluminum layer 102A to control the rate of diffusion of the acid andthereby control the response rate of cumulative indicator 102.

Dual indicator 100 may be fabricated by supplying substrate 102D thatmay already have a desirable color or appearance or may be coated with amaterial or ink to achieve a desirable appearance. To substrate 102D isapplied aluminum layer 102A. A dissolvable or removable material otherthan aluminum could be used instead of or in addition to aluminum. Ontop of layer 102A is applied layer 102B that includes a laminatingadhesive and etchant or other material selected to interact with andremove or etch away the material of layer 102A. Barrier layer 102C mayoptionally be included between layer 102A and layer 102B to modulate theinteraction between the two layers. These layers together may constitutecumulative indicator 102.

On top of cumulative indicator 102 may be applied peak thresholdindicator 101, which may be separately fabricated and then applied tocumulative indicator 102 or the various layers of peak thresholdindicator 101 may be sequentially applied on top of the layers ofcumulative indicator 102. Above layer 102B is applied meltable solidcoating 101A that may be secured between one or both of barrier coatings103 and 105. On top of meltable solid coating 101A, or alternativelybarrier coating or transparent film 105, may be applied reference ring104.

The underside or backing of dual indicator 100 may include adhesive 106that is protected prior to application by release liner 107.

FIGS. 10A-10M illustrate variations on the embodiment illustrated inFIG. 10. It is to be understand from these various embodiments that thelayers illustrated in FIG. 10 could be arranged in number of ways andcould be sized to cover all or just a portion of underlying layers.

The embodiment illustrated in FIG. 10A is substantially identical to theembodiment of FIG. 10 except that optional barrier coating 103 couldalso include or be replaced with a transparent film. Moreover, in lieuof film substrate 102D, a color coating 102E could be used with anoptional transparent film 102F positioned between color coating 102E andaluminum layer 102A. FIG. 10A also makes clear that label adhesive 106and release liner 107 are optional features that need not be included.

The embodiment illustrated in FIG. 10B is substantially identical to theembodiment of FIG. 10A except that the relative positions of colorcoating 102E optional film 102F are reversed such that color coating102E is positioned between aluminum layer 102A and optional film 102F.

The embodiment illustrated in FIG. 10C is substantially identical to theembodiment of FIG. 10A except that transparent film 105 is applied overinstead of under reference ink 104. This means that reference ink 104 isadjacent to meltable solid coating 101A.

The embodiment illustrated in FIG. 10D is substantially identical to theembodiment of FIG. 10C except that meltable solid coating 101A isapplied between reference ink 104 and transparent film 105. In thisembodiment, meltable solid coating 101A occupies at least some of thespace bordered by reference ink 104, which may be a circle or a squareor some other configuration that allows a center portion and any visibleunderlying layers to be compared against a border of reference ink 104.

The embodiment illustrated in FIG. 10E is substantially identical to theembodiment of FIG. 10D except that meltable solid coating 101A isapplied primarily to the area bordered by reference ink 104, althoughsome of meltable solid coating 101A is shown as applied onto a portionof reference ink 104.

The embodiment illustrated in FIG. 10F is substantially identical to theembodiment of FIG. 10D except that the positions of meltable solidcoating 101A and transparent film 105 have been reversed so thattransparent film 105 is positioned between meltable solid coating 101Aand reference ink 104. Moreover, color coat 102E and optional film 102Fhave been replaced with substrate 102D.

The embodiment illustrated in FIG. 10G is substantially identical to theembodiment of FIG. 10F except that meltable solid coating 101A isapplied to only a portion of transparent film 105. This portion mayinclude the area substantially above the space bordered by reference ink104.

The embodiment illustrated in FIG. 10H is substantially identical to theembodiment of FIG. 10D except that reference ink 104 is located betweenlayer 102B and optional barrier coating 102C.

The embodiment illustrated in FIG. 10I is substantially identical to theembodiment of FIG. 10H except that reference ink 104 is located insubstantially the same layer as aluminum layer 102A. In some embodimentsat least some of aluminum layer 102 is located on top of at least aportion of reference ink 104.

The embodiment illustrated in FIG. 10J is substantially identical to theembodiment of FIG. 10I except that aluminum layer 102A and all thelayers above it are positioned substantially above the area bordered byreference ink 104 although the layers may overlap reference ink 104 atleast partially. Moreover, aluminum layer 102A may be positioned atleast partially within reference ink 104.

The embodiment illustrated in FIG. 10K is substantially identical to theembodiment of FIG. 10J except optional barrier coating 102C and thelayers above it extend beyond the are substantially above the open areabetween reference ink 104. This means that aluminum layer 102A is fullyor substantially encased between optional barrier coating 102C,reference ink 104, and optional transparent film 102F.

The embodiment illustrated in FIG. 10L is substantially identical to theembodiment of FIG. 10J except reference ink 104 is positioned insubstantially the same layer as color coating 102F, such that colorcoating 102F and all the layers above it are positioned substantiallyabove the area between reference ink 104.

The embodiment illustrate in FIG. 10M is substantially identical to theembodiment of FIG. 10L except that only aluminum layer 102A and colorcoating 102E are positioned substantially above the area betweenreference ink 104. Optional barrier coating 102C is positioned abovealuminum layer 102A and substantially encapsulates both aluminum layer102A and color coating 102F.

Further example embodiments of the invention may include protection fromultraviolet radiation, if desired. Ultraviolet radiation may interferewith the response of a dual-function heat indicator, in some cases, andmay degrade a variety of materials. Ultraviolet protection may beprovided in any one or more of various ways. For example, one or moreultraviolet filter materials may be included in transparent film 26. Inanother example embodiment, a visibly transparent ultraviolet-filteringlayer, such as a printed ultraviolet-absorbent ink may be disposeddirectly over active surface 20. Such a construction is described inU.S. Pat. No. 7,682,830 to Prusik et al. A further way to provideprotection against ultraviolet radiation is for the adhesive used toattach an outer protective transparent film, such as transparent film26, if a transparent film and adhesive are employed, to include one ormore ultraviolet filters. Such a construction is described in U.S.Provisional Patent Application No. 61/611,319 to Smith et al. Theultraviolet protection measures described in U.S. Pat. No. 7,682,830 andApplication No. 61/611,319 may be employed in an example embodiment ofthe dual-function heat indicator, as will be apparent to a person ofordinary skill in the art

Various dyes or other colorants or optically distinctive materials maybe dissolved in, or otherwise incorporated in a meltable solid employedin the practice of the example embodiment of the invention to give themeltable solid a distinctive inherent appearance, as will be known orapparent to a person of ordinary skill in the art, in light of thisdisclosure, or will become known or apparent in the future. Examples ofsuitable dyes include Oil Black BS (C. I. Solvent Black 7 mixed withstearic acid, Orient Corporation of America, Kenilworth, N.J.) and OilRed O dye (Sigma-Aldrich, St. Louis, Mo.). Optionally the dye or othercolorant or optically distinctive material and/or the meltable solid maybe opaque so that the peak exposure indicator has an opaque appearanceafter activation. Some other optically distinctive materials that may beemployed include pigments, fluorescent materials, pearlescent materials,iridescent materials and mixtures of two or more of the foregoingoptically distinctive materials.

An example embodiment of a method of preparing a peak exposure indicatoremploying a meltable particulate colored material 84 configured intolight-scattering particles for inclusion in an example embodiment of adual-function heat indicator will now be described. The method includesdissolving a relatively small amount of dye in a meltable solid formedof an organic material such as a wax, for example from about 0.001percent to about 1 percent by weight of the dye based upon the weight ofthe resultant meltable colored material. The meltable solid may be lightin color, for example white or pale yellow, and optionally, may betransparent or translucent. Sufficient dye may be employed to color themeltable solid while avoiding an excess, for example, 0.02 percent byweight of Oil Black BS (C. I. Solvent Black 7 mixed with stearic acid),which is an intense black powder, may be dissolved in heneicosane.Heneicosane is a linear C₂₁ light-colored, or whitish, alkane having amelting point of about 40° C. that is available from Sigma-Aldrich (St.Louis, Mo.).

This method may also include preparing fine particles of the meltablecolored material having an average particle size providing alight-colored appearance of the dyed wax may be prepared by any suitablesize-reduction procedure. Some examples of suitable size-reductionprocedures include emulsifying the meltable colored material at atemperature above its melting point, when the material is molten, thencooling the resultant emulsion, or precipitating the molten coloredmaterial into cold water, or another non-solvent, with vigorous mixing.Other suitable size-reduction procedures will be known or apparent to aperson of ordinary skill in the art, in light of this disclosure, orwill become known or apparent in the future. The sizing procedure may beconducted to yield an average particle size in the range of from about50 nm to about 5 μm, in the range of from about 100 nm to about 2 μm, inthe range of from about 200 nm to about 700 nm, or in the range of fromabout 200 nm to about 350 nm. The parameters of the sizing procedure maybe varied to provide a desired degree of light scattering, whichoptionally may be determined by the desired lightness of the meltableparticulate colored material so prepared. The resultant particles mayhave an average particle size of at least about 50 nm, 10 nm, or 200 nm,and of not more than about 350 nm, 700 nm, 2 μm or 5 μm.

The method may further include formulating a coating compositionincorporating the meltable particulate colored material and applying thecoating composition to the substrate. Other ingredients such as thermalsensitizers, binders, pigments, lubricants, dispersants, antifoamagents, and the like, including the materials described herein,optionally, may also be employed in the coating composition. Ifemployed, such other ingredients should have optical propertiescompatible with the intended optical performance of the peak exposureindicator.

The coating composition may be prepared by a method such as is describedherein for preparing a peak indicator composition except that the firstreactant and the second reactant are omitted. Thus, the color-formingfunction of the first reactant and the second reactant may be replacedby the meltable particulate colored material. Using the previouslydescribed example of a black-dyed heneicosane wax, the dyed waxparticles may have a light color, for example, whitish, due to lightscattering, prior to activation of the peak exposure indicator. However,upon melting of the heneicosane wax, in response to exposure to anambient temperature at, or above, about 40° C., the melting point of theheneicosane wax, the inherent black color of the dyed wax particlesquickly becomes apparent. Promptly after melting the small dyed waxparticles coalesce and cease scattering light revealing their inherentcolor.

In a further aspect, the example embodiment of the invention provides aheat event indicator for monitoring ambient heat exposure to atemperature traversing a threshold temperature. The heat event indicatormay include a substrate and a coalesceable particulate colored materialsupported by the substrate. The coalesceable particulate coloredmaterial may have an average particle size imbuing the coalesceableparticulate indicator material with a light color, the light color beingattributable to scattering of visible light by the coalesceable coloredmaterial particles. Coalescence of the coalesceable particulate coloredmaterial may cause the material to darken in color, and the darkeningmay be induced by an ambient heat exposure event that reaches atemperature traversing the threshold temperature. Thus, the heat eventindicator may indicate the occurrence of the ambient heat exposure eventby changing color.

In such a heat event indicator, the threshold temperature may be a peaktemperature and the coalesceable particulate colored material may bemeltable and may melt in response to the ambient heat exposure event.Such embodiments of heat event indicator may be similar to adual-function heat indicator as described herein wherein the peakexposure indicator component of the dual-function heat indicator employsa light-scattering meltable particulate colored material and nocumulative exposure indicator is present. The coalesceable particulatecolored material may be similar to a meltable particulate coloredmaterial and may have an average particle size as described for themeltable particulate colored material. Further, the coalesceableparticulate colored material may provide a color change, in response toa suitable heat event, without reacting with a color developer or otherchemical reactant and without significant migration after melting. Sucha heat event indicator may function as a peak exposure indicator.

Alternatively to a peak temperature, the threshold temperature may be afreezing temperature, the heat event indicator may include a dispersionof the coalesceable particulate colored material in an aqueous liquidmedium, wherein the dispersion collapses and the coalesceableparticulate colored material coalesces in response to the ambient heatexposure event. Such a heat event indicator may include a transparentlayer, a substrate, an adhesive layer, and a liner, all as describedherein as one or more optional components.

Initially the inherent color of the coalesceable particulate coloredmaterial may be masked by light scattering attributable to the averageparticle size of the coalesceable particulate colored material providingthe dispersed material a lighter appearance, for example, white, whitishor, in the case of an inherently black coalesceable particulate coloredmaterial, pale grey, possibly. Also, the light scattering-inducedappearance may be opaque. Freezing and/or thawing of the aqueous liquidmedium may induce coalescence causing the particles of colored materialto reveal their inherent color, which may be darker or more intense thanthe initial color. After freezing, the colored material may also obscureany background behind the colored material so that the background maynot be viewed accurately through the colored material. As described forthe meltable particulate colored material, the coalesceable particulatecolored material may change color without employing a color developer ora side-chain crystallizable polymer or engaging in a chemical reaction.Such a heat event indicator may function as a freeze indicator.

The dispersed coalesceable particulate colored material may have variouscomponents, as will be known or apparent to a person of ordinary skillin the art, in light of this disclosure, or will become known orapparent in the future. In one example embodiment, the colored materialmay include, or consist of, a dye, such as described herein, dissolvedin a suitable hydrophobic liquid, such as an oil, and the oil may bedispersed in the aqueous liquid medium as appropriately sized droplets,providing an emulsion. Suitable oils and other useful characteristicsthat such a freeze indicating embodiment of the heat event indicatordescribed herein are described in U.S. Pat. No. 8,430,053B2 by Taylor etal.

In another example embodiment, the colored material may include a finelydivided pigment dispersed in the oil droplets, in place of, or togetherwith the dissolved dye. In a further example, pigment particles of anappropriate size to cause light scattering may provide the coloredmaterial and no oil or dye need be employed.

Materials

Various materials that may be employed in the practice of the exampleembodiments of the invention detailed above will now be described. Itwill be known or apparent to a person of ordinary skill in the art, inlight of this disclosure, other materials that may also be suitable.

Liner.

Suitable liner materials for dual-function heat indicator embodiments ofthe example embodiment of the invention include various papers andsynthetic polymer materials, any of which may be coated to facilitateremoval of a dual-function heat indicator having an adhesive-coatedsubstrate from a liner. Other suitable liner materials will be known orapparent to a person of ordinary skill in the art. Some suitable papersinclude kraft paper, calandered kraft paper, machine glazed paper, andclay-coated paper. Some suitable synthetic polymeric materials includepolyethylene terephthalate, biaxially oriented polypropylene andpolyolefins. Some suitable coating materials include polyvinyl alcohol,silicones, and other materials having low surface energy.

Substrate.

A substrate employed in an example embodiment of the dual-function heatindicator may be fabricated from a variety of materials includingimprintable or coatable materials, for example, a synthetic plasticsheet or film. Other suitable substrate materials will be known orapparent to a person of ordinary skill in the art. Suitable substratesmay be flexible or rigid, transparent or opaque, optionally may becolored, and may be lamina in form, or sheet-like. White substrates mayhelp provide contrast with an end point appearance if the cumulativeheat indicator and peak exposure indicator are initially transparent.Also, where the indicators are initially transparent, distinctiveindicia, or a graphic, for example a check mark, or other suitablehuman-readable or machine-readable indicia may be included on thesubstrate, and may be obscured after the dual-function heat indicatortransitions to an end point appearance. For mass production, substratesfor individual indicators may be cut from sheets, strips, or continuouswebs. Some examples of useful substrate materials include, withoutlimitation, polyethylene, polypropylene, polycarbonate, polyester,polyamide, polyurethane, polyvinyl chloride, polyvinylidene chloride,cellulose-derived materials, aluminum foil, paper, coated paper, and alaminated structure including a layer or layers of any one or more ofthe foregoing materials.

A further example of a suitable substrate material is a corona-treated,dimensionally stable, flexible, white, opaque polyolefin film such as issupplied under the trademarks FAS SON® PRIMAX®, product code 250, byAvery Dennison Corporation, Pasadena, Calif.

Optionally, in example embodiments of the invention where a substratecontacts an adhesive material, the substrate surface may be sealed orotherwise treated to inhibit migration of the adhesive or components ofthe adhesive through the substrate material. Alternatively, or inaddition a substrate material, or an additional material layer, thatresists such migration may be employed.

Cumulative Exposure Indicator.

The cumulative exposure indicator employed in an example embodiment ofthe dual-function heat indicator may be or may include a heat-sensingagent that may change appearance in response to heat. The heat-sensingagent may darken in color with continued heat exposure, and the degreeof darkening may provide a measure of the cumulative heat exposure.Alternatively, the heat-sensing agent may exhibit another appearancechange, for example, lightening, a change in hue, or another opticallyreadable indication. The heat-sensing agent may include one or moreheat-sensitive compounds, some of which are described elsewhere herein.

The cumulative exposure indicator may be manufactured by applying asuitable indicator ink including the heat-sensing agent to a substrate,then drying the indicator ink on the substrate, as described elsewhereherein. The cumulative exposure indicator may include the dried residueof the ink and the substrate supporting the ink residue. The indicatorink may include a liquid vehicle; a film-forming agent dissolved in theliquid vehicle, an insoluble heat-sensing agent dispersed in the liquidvehicle and various optional ingredients for example one or moredispersants, antiactinic agents, colorants, preservatives, fragrances orother additives. An example of a suitable liquid vehicle is an organicsolvent such as isopropanol, or ethyl 3-ethoxypropionate. An example ofa suitable film-forming agent is nitrocellulose. Some examples ofsuitable indicator inks that may be employed in dual-function heatindicator embodiments of the example embodiment of the invention andtheir manufacture are described in U.S. Pat. No. 8,067,483 and thepatent documents referenced therein.

Some useful heat-sensing agents may provide an irreversible indicationof cumulative temperature exposure over time, and may provide along-lasting record of the heat exposure. The cumulative heat responseof the heat-sensing agent may be such that the heat-sensing agent maymonitor heat exposure as an integral of temperature over time. Further,the heat-sensing agent may be heat-sensitive and may have usefulindicator reactivity at ambient temperatures likely to be encountered bya monitored host product, for example, temperatures in the range of fromabout 0° C. to about 60° C.

The heat-sensing agent may include, or consist of, any of a variety ofchemical components. One useful example embodiment of heat-sensingagents includes one or more thermally sensitive diacetylenic compounds,for example, an individual diacetylenic compound or a co-crystallizedmixture of two diacetylenic compounds.

The diacetylenic compound, or compounds, may polymerize to provide acolor change or another optically readable indication. Diacetyleniccompounds useful in the practice of the example embodiment of theinvention include polymerizable diacetylenic compounds including atleast two conjugated acetylenic groups, i.e. groups having the formulaSome exemplary polymerizable diacetylenic compounds that may be employedinclude substituted 2,4-hexadiyn-1,6-bis(alkylurea) compounds whereinthe alkyl group has from 1 to 20 carbon atoms, the foregoingdiacetylenic bis(alkylurea) compounds wherein the alkyl substituents arelinear, and co-crystallized mixtures of any two or more of the foregoingbis(alkylurea) compounds. The two alkyl groups in any of the foregoingdiacetylenic bis(alkylurea) compounds may be the same and thebis(alkylurea) compounds may be symmetrically substituted. Someparticular examples of the foregoing diacetylenic bis(alkylurea)compounds include ethyl, propyl, butyl, octyl, dodecyl andoctyldecyl-substituted 2,4-hexadiyn-1,6-bis(alkylurea) compounds, linearisomers of these compounds and co-crystallized mixtures of two or moreof the linear isomers.

Some further example embodiments of useful diacetylenic compounds thatmay be employed in example embodiments of the dual-function heatindicator are disclosed in U.S. Pat. Nos. 3,999,946; 4,189,399 and4,384,980 to Patel; U.S. Pat. Nos. 4,789,637 and 4,788,151 to Preziosiet al.; U.S. Pat. Nos. 6,924,148; 7,019,171; 7,161,023; and 8,067,483 toPrusik, or Prusik et al.; U.S. Patent Application Publication No.2009/0131718 by Baughman et al.; and U.S. Patent Application PublicationNo. 2011/0086995 by Castillo Martinez et al., among which documents thelatter three were cited previously herein. Some useful heat-sensingagents may include one or more diacetylenic compounds and areactivity-enhancing adjuvant, for example, as described in U.S. Pat.No. 8,067,483. Useful diacetylenic compounds are also described at page36, line 10 to page 39, line 4 of Provisional Patent Application No.61/611,319 filed Mar. 15, 2012.

Other chemistries and technologies that may be used as, or in, aheat-sensing agent for a cumulative exposure indicator component of anexample embodiment of a dual-function heat indicator include:

-   -   heat-sensitive dyes that may be activated or de-activated by        exposure to ultraviolet radiation to provide or remove color;    -   dyes that are triggered to exhibit color, or change color, by pH        changes, for example, as disclosed in U.S. Pat. No. 4,917,503 to        Bhattacharjee;    -   a reversibly photochromic compound, such as a compound that may        undergo photo-induced coloration by irradiation with light or        ultraviolet radiation, followed by a time- and        temperature-dependent decoloration, for example, a spiroaromatic        compound, some examples of which are described in U.S. Patent        Application Publication No. 2010/0034961 by Tenetov et al. (“US        2010/0034961”); and    -   enzyme-based sensors such as are described in U.S. Pat. No.        6,642,016 to Sjoholm, et al. or U.S. Pat. No. 4,284,719 to        Agerhem, et al.

Some further example embodiments of useful cumulative exposureindicators that may be employed in practicing the example embodiment ofthe invention are described in U.S. Pat. No. 5,622,137 to Lupton et al.,U.S. Pat. No. 5,756,356 to Yanagi, et al., U.S. Pat. No. 6,043,021 toManico et al., and International Publication No. WO 99/39197 by Haareret al. Still further suitable cumulative exposure indicators that may beemployed in practicing the example embodiment of the invention will beknown or apparent to a person of ordinary skill in the art, in light ofthis disclosure, or will become known or apparent in the future.

Peak Exposure Indicator.

The peak exposure indicator may be a meltable solid and may include afirst reactant and a second reactant that are chemically co-reactable toprovide a color change. Further the peak exposure indicator may be areactant, it may include one or more reactants, it may separate thereactants, or it may be the agent which on melting enables the reactantsto react. Optionally, a thermal sensitizer may also be included. Thefirst reactant and the second reactant may be present in the same layerof an example embodiment of the dual-function heat indicator.Alternatively, the first reactant and the second reactant may be presentin different layers of an example embodiment of the dual-function heatindicator. The color-changing chemical reaction may be induced inresponse to an ambient heat exposure peak and may be irreversible.Optionally, a single reactant may provide suitable peak exposureindicating functionality.

The peak exposure indicator may include additional ingredients thatcontribute to the useful functioning of an example embodiment of thedual-function heat indicator. Some examples of possible additionalingredients, which may be employed individually or in combination,include pigments, binders, lubricants, dispersants, antifoam agents, andother additives that may modify one or more characteristics of the peakexposure indicator, without detracting from its performance, as will beknown or apparent to a person of ordinary skill in the art, in light ofthis disclosure, or will become known or apparent in the future. Suchadditional ingredients, if present, also may be included in a singlelayer with the first reactant and the second reactant.

By way of example, the first reactant may be a color precursor, or colorformer, and the second reactant may be a color developer. Many suitablecolor precursors and color developers are known and may be employedalone or in combinations of two or more compatible compounds. Somesuitable color-forming reactants, including some color precursors andcolor developers, are described in U.S. Pat. No. 8,430,053 to Taylor etal., for example, at paragraphs [0199] to [0248]. Suitable color-formingreactants are also described in U.S. Pat. No. 5,741,592 to Lewis et al.and U.S. Patent Application Publication No. 2008/0233290 to Ward-Askeyet al.

Some specific examples of useful color precursors include: specialtymagenta 20, ODB-1 and ODB-2 (available from Emerald Hilton Davis,Cincinnati, Ohio); and PERGASCRIPT® Red 16B (available from BASF,Charlotte, N.C.). Upon development, specialty magenta 20 andPERGASCRIPT® Red 16B produce an intense magenta color, and colorprecursors ODB-1 and ODB-2, become black.

Some further examples of useful color precursors include: benzoyl leucomethylene blue; malachite green lactone; N-2,4,5-trichlorophenylleucoauramine; additional compounds that are red when developed including3-diethylamino-6-methyl-7-chlorofluoran, and3,6-bis(diethylamino)fluoran-γ-(4′-nitro)-anilinolactam; additionalcompounds that are black when developed including3-diethylamino-6-methyl-7-anilinofluoran and3-(N-ethyl-N-isoamylamino)-6-methyl-7-anilinofluoran; and compounds thatare orange when developed including 3-cyclohexylamino-6-chlorofluoranand 3-diethylamino-6,8-dimethylfluoran.

Still further examples of useful color precursors include:3,3-bis(p-dimethylaminophenyl)-phthalide;3,3-bis(p-dimethylaminophenyl)-6-dimethylaminophthalide (crystal violetlactone); 3,3-bis(p-dimethylaminophenyl)-6-diethylaminophthalide;3,3-bis(p-dimethylaminophenyl)-6-chlorophthalide;3,3-bis(p-dibutylaminophenyl)-phthalide;3-(N—N-diethylamino)-5-methyl-7-(N,N-dibenzylamino) fluoran;3-dimethylamino-5,7-dimethylfluoran; 3-diethylamino-7-methylfluoran;3-(2′-hydroxy-4′-dimethylaminophenyl)-3-(2′[-methoxy-5′-chlorophenyl)phthalide;3-(2′-hydroxy-4′-dimethylaminophenyl)-3-(2′-methoxy-5′-nitrophenyl-phthalide;3-(2′-hydroxy-4′-diethylaminophenyl)-3-(2′-methoxy-5′-methylphenyl)phthalide;and3-(2′-methoxy-4′-dimethylaminophenyl)-3-(2′-hydroxy-4′-chloro-5′-methylphenyl)-phthalide.

Some specific examples of useful color developers include oil-solublereducing agents; oxalic acid; phosphite esters; hydroxybenzoic acidesters; hydrohydroquinone, hydroquinone derivatives such asdimethyhydroquinone, di-tert-butyl hydro quinone, otherdialkylhydroquinones, and the like, 3-ethoxyphenol;1,2-diethyl-3-hydroxybenzene; 1,3-diethyl-2-hydroxybenzene;2,2′-methylenebis(3,4,6-trichlorophenol); meltable, orsensitizer-soluble, primary and secondary amines having low watersolubility, for example, 4-butyl-aniline; phenol derivatives; organicacids; acid clays; FULACOLOR™ XIV reactive acid hectorite clay(available from Rockwood Additives, Widnes, UK); phenolic resins;phenol-acetylene resins; polyvalent metallic salts of phenolic resins;HRJ 2053 zinc-including modified alkyl phenolic resin (available from SIGroup, Schenectady, N.Y.); zinc salicylate, zinc salicylate resin;4,4′-isopropylidenebisphenol (also known as bisphenol A);1,7-di(hydroxyphenylthio)-3,5-dioxaheptane, 4-hydroxyethyl benzoate,4-hydroxydimethyl phthalate; monobenzyl phthalate;bis-(4-hydroxy-2-methyl-5-ethylphenyl)sulfide,4-hydroxy-4′-isopropoxydiphenylsulfone; 4-hydroxyphenylbenzenesulfonate;4-hydroxybenzoyloxybenzylbenzoate;bis-(3-1-butyl-4-hydroxy-6-methylphenyl)sulfone; p-tert-butylphenol; andpolymers based on bisphenol A.

Thermal Sensitizers.

A thermal sensitizer optionally may be employed in an example embodimentof the peak exposure indicator. A thermal sensitizer may be selected tohave a melting-point that causes the peak exposure indicator to at leastbegin to melt at a desired response temperature, initiating thecolor-changing reaction.

The thermal sensitizer may be mixed with the first reactant and thesecond reactant and the resultant mixture may have a melting-point thatis the same as the desired response temperature or within about 2° C.,or about 5° C. of the desired response temperature of the peak exposureindicator. The mixture may be an intimate admixture of the ingredientsin particulate form. Alternatively, the melting-point of the thermalsensitizer may be the same as the desired response temperature or may bewithin about 2° C., or about 5° C. of the desired response temperature.Where no thermal sensitizer is employed, at least one of the firstreactant and the second reactant may have a melting point that is thesame as the desired response temperature or is within about 2° C., orabout 5° C. of the desired response temperature.

The thermal sensitizer, if employed, may help control the melting-pointof the peak exposure indicator, for example by lowering themelting-point and may initiate or accelerate the color-forming reaction.

Some materials useful as thermal sensitizers in the practice of theexample embodiment of the invention may include fatty acid amidecompounds, acetamide, stearic acid amide, linolenic acid amide, lauricacid amide, myristic acid amide, methylol compounds,methylene-bis(stearamide), ethylene-bis(stearamide), p-hydrozybenzoicacid esters, methyl p-hydroxybenzoate, n-propyl p-hydroxybenzoate,isopropyl p-hydroxybenzoate, benzyl p-hydroxybenzoate, diphenoxyethane,aryl-substituted biphenyls, alkyl-substituted biphenyls, p-benzylbiphenyl, toluidide phenyl, heptadecanol, 4-methoxyphenol, pentadecanol,2,4-di-tert-butyl phenol, benzophenone, diethyl terephthalatehydroxynaphthoates, alkyl alcohols, and dibenzyl oxalate any of whichmaterials may be used alone or in combination. Useful thermalsensitizers optionally may include a wax and/or a fatty acid.

Some materials useful as binders in the practice of the exampleembodiment of the invention include starches, celluloses, natural andsynthetic gelatins, methoxycellulose, hydroxyethylcellulose,carboxymethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone,polyacrylamide, polyacrylic acid, copolymers of vinyl chloride and vinylacetate, polybutylmethacrylate, and water emulsions of polystyrene. Twoor more binder materials may be employed. The binder, if employed, maybe water insoluble, water soluble or a mixture of one or morewater-insoluble binder materials, and one or more water-soluble bindermaterials.

Some materials useful as pigments in the practice of the exampleembodiment of the invention include calcium carbonate, silica, titaniumdioxide, alumina, magnesia, talc, barium sulfate and aluminum stearate.

Some materials useful as lubricants in the practice of the exampleembodiment of the invention include linseed oil, tung oil, wax,paraffin, and polyethylene wax.

Other suitable materials will be known or apparent to a person ofordinary skill in the art, in light of this disclosure, or will becomeknown or apparent in the future.

Dual-function exposure indicators according to the example embodiment ofthe invention may usefully be employed to monitor the condition of anyof a wide range of heat-sensitive host products. Host products that maybe monitored include, in addition to vaccines: temperature-sensitivehealth care products, for example, drugs, medicaments, pharmaceuticals,pharmaceuticals incorporating a polypeptide, a nucleic acid or cellularmaterial, temperature-sensitive medical devices, temperature-sensitiveprophylactics and the like; biological materials for industrial ortherapeutic uses, for example cultures, organs, and other human oranimal body parts, blood, and perishable blood products; diagnosticdevices, diagnostic kits containing perishable products, and perishablediagnostic ingredients; batteries, battery-containing devices,battery-containing appliances; fresh or prepared foodstuffs, includingfish, meats, dairy products, fruits, vegetables, baked goods, desserts,and the like; food service products, including restaurant service foods;gourmet food products; perishable animal foods; cut and uncut flowers;plants; cosmetics, for example cosmetics containing biologicals or otherlabile or perishable ingredients; beauty aids; perishable industrialproducts; paint; solder; perishable munitions and ordnance; andperishable decontamination packs and products.

A dual-function exposure indicator according to the example embodimentof the invention may be associated with a host product in a variety ofways, for example by adhering, tying, looping, stapling or otherwiseaffixing the dual-function exposure indicator, or a label or tagembodying the dual-function exposure indicator, to a desired hostproduct, either directly to a host product, or to a package containingthe host product, or to a package, carton, box or other containercontaining a number of host product items. Also, the dual-functionexposure indicator, label, or tag, may be inserted in a host productpackage, carton, or other container for one or more host product items.

EXAMPLES Example 1: Manufacture of Dual Heat Indicator Prototypes

Prototype indicators were manufactured by laminating VVM14-likecumulative heat indicators, printed on clear film, to a commerciallyavailable thermal paper or pre-manufactured thermal paper. VVM14-likecumulative heat indicators are prototype cumulative heat indicatorsformulated to respond to approximately 14 days at 37° C., and intendedto be similar to the commercially available HEATmarker VVM14, availablefrom Temptime Corporation. VVM14 has a well-characterized temperatureresponse profile and is manufactured to meet World Health Organizationrequirements provided in PQS Performance Specification, Vaccine VialMonitor WHO/PQS/E06/IN05.2, 26 Jul. 2011. It responds in 14 days at 37°C., in 90 days at 25° C., and >3 years at 5° C. The prototype indicatorswere manufactured on a Gallus 250 I printing press. Two trials wereperformed, the latter was to evaluate a thinner version of the clearpolyester film as an improvement. Neither set of prototypes were die-cuton the Gallus press to avoid the cost of obtaining die tools, howeverthey were manually die-cut to produce samples for demonstration. Thetrials demonstrated that the process and the prototype construction werefeasible. The prototypes were able to detect excessive heat exposure andstill monitor the cumulative effects of heat and time below thethreshold limit.

The first trial used DuPont Teijin Films™ Melinex® 561, a 0.005 inchthick, clear polyester film. This film is chemically treated on bothsides to accept solvent-based inks and provide a clean cut whendie-cutting. The second prototype trial utilized Transilwrap Companygeneral purpose Oriented Polyester, a 0.00092 inch thick, clearpolyester film treated on one side for solvent-based printing. GothamInk's “Gotham baseline lavender”, a solvent-based flexographic inkadjusted to obtain an exact color match with the indicator ink by addingsuitable quantities of Gotham Series opaque white, Gotham Seriesmagenta, and Gotham Series cyan inks was utilized for the reference ringink. The indicator “active” ink was manufactured in-house by dispersing“KE” (2,4-hexadiyn-1,6-bis(ethylurea) powder in a solvent-basednitrocellulose ink, according to the procedures outlined in U.S. Pat.No. 8,067,483. The quantity of KE in the ink and the amount of inkapplied to the polyester film were chosen in order to achieve a colormatch between the temperature-sensitive active ink and thetemperature-insensitive reference ink after about 14 days at 37° C.

FLEXcon's FLX055158 FLEXmount DFM-100 Clear V-224 150 Poly H-9 V-224 150Poly H-9 laminate was utilized. This laminate consists of a clearpolyester carrier film, coated both sides with a water-based permanentpressure-sensitive adhesive. It was used for laminating the thermalpaper to the printed clear polyester film. The laminate was providedwith release liners on both sides, which were removed during prototypemanufacture. Earlier screening demonstrated that solvent based adhesivesmay affect the ability of the thermal paper to darken as such thiswater-based adhesive was selected because it did not show that effect.However, there may be suitable combinations of solvent-based adhesiveswith thermal paper that do not show this effect. The polyester carrierfilm and the two layers of adhesive add 0.003 mm to the laminatedstructure thickness. Each adhesive layer is 0.001 mm thick on a 0.001 mmPET carrier film. If further reduction in stiffness and thickness arerequired in the product, this laminating film could be replaced with anunsupported adhesive layer applied as a transfer tape product.

The thermal paper utilized was Mactac DTR 9902 thermal label paper,consisting of high sensitivity topcoated IR scanable direct thermalpaper with a high tack permanent acrylic emulsion adhesive, suppliedwith a semi-bleached calendared kraft liner. The thermal paper thicknessis described as typically 0.0034 in and the adhesive adds another 0.0007in to the thickness. The adhesive is designed for use on medical vialsand has an average peel strength of 2.4 lbs/in. The adhesive wasdesigned to adhere to metal, plastic and glass.

The process of manufacturing included first pass through the Galluspress to form a laminate between the thermal paper and the dual sideadhesive coated laminating film. The thermal paper was placed on theunwind roller with the active surface facing up. The corona treater anddryers were off and cold for this step. If either were on, it could havecaused the thermal paper to darken. At the laminating station, theFlexmount DFM was mounted so that one liner was removed and the newlyrevealed adhesive was placed in contact with the thermal paper's activesurface. The resulting laminated product was rewound so that it could beused on the laminating station in the second pass.

The second pass at the press included the clear polyester film beingplaced at the unwind. In the first trial, there was no need to becareful of which side would be printed because both sides werechemically treated for solvent ink acceptance. In the second trialhowever, the clear polyester film had the chemically treated side onlyon the outside surface of the roll, so care was taken to mount the rollso that the outside would be printed.

In order to manufacture the cumulative indicator portion of the dualindicator, the reference ring was printed onto the clear polyester firstfollowed by two printed layers of the active ink.

The rolls made in the first pass through the press were mounted at thelaminating station so that the release liner from the other adhesivesurface of the dual side adhesive coated laminating film was removed.The newly revealed adhesive came into contact with the printedcumulative indicator on the clear polyester film. The entire laminatewas flipped so that the clear polyester film was on top. Thisconfiguration would then be ready to be die-cut through the clearpolyester down through to the release liner of the thermal paper. Nodie-cutting was performed in these trials.

The results for the samples from the first prototype trial using DuPontTeijin Films™ Melinex® 561 may be seen in FIGS. 10-13. Three types ofsamples were obtained: the dual indicator construction, just the thermalpaper with the laminating film and clear film on top, and just thecumulative indicator portion of the dual indicator (i.e. the active andreference inks printed onto the clear film). Optical densitymeasurements were performed using an X-Rite 504 Spectrodensitometer andthe cyan, magenta, yellow and black measurements were recorded. Onlycyan optical density measurements are reported and were used forperformance analysis comparable to assessments of the active ink portionof the cumulative indicator. The reference ring had a cyan OD value ofabout 0.50, which was unaffected by temperature exposure. The threesample types were affected by temperature, and in each case theindicator “end point” for any given temperature may be represented bythe amount of time for the indicator to reach an OD of about 0.50.

Ten samples of each phase were tested in isothermal water baths capableof controlling the temperature to ±0.1° C. The samples were mounted ontowhite cardstock then double sealed in aluminum and plastic pouches andheld at various temperatures for a series of specified times,periodically removing them from the baths to measure the OD change overtime. At higher temperatures, the samples were double bagged in clearplastic so that the response could be observed directly.

At 90° C., the indicator response was dominated by the thermal paperwhich blackens within 1 second of immersion in the water bath. There wasno change in the VVM14-like portion of the indicators in this timeframe. Endpoint, defined as when the cyan absolute OD reaches 0.50, wasnot reached for the cumulative indicators until almost 40 minutes.

At 80° C. the results are similar to those presented for 90° C. exceptthat the thermal paper darkening took a little longer, 10 seconds, andthe maximum OD was slightly lower. The cumulative indicators did notreach 0.5 OD until nearly 3 hours. In general, at temperatures of 50° C.and below, the thermal paper showed very little response and thereforethe dual heat indicator responded essentially as a cumulative indicator.

Example 2: Dual Heat Indicator Protoypes to Illustrate ExampleEmbodiment Demonstrated in FIG. 7

Hand-made prototype dual heat indicators were made by laminatingVVM14-like cumulative heat indicators, printed on clear film, to acommercially or pre-manufactured available threshold indicator. Thecumulative indicator component was made by printing a color-changing“active” diacetylene ink and a static, “reference ink” onto DuPontTeijin Films™ Melinex® 561, a 0.005 inch thick, clear polyester film,using a Gallus 250 I printing press. The “active” ink was manufacturedin-house by dispersing “KE” (2,4-hexadiyn-1,6-bis(ethylurea) powder in asolvent-based nitrocellulose ink, according to the procedures outlinedin U.S. Pat. No. 8,067,483. The quantity of KE in the ink and the amountof ink applied to the polyester film were chosen in order to achieve acolor match between the temperature-sensitive active ink and thetemperature-insensitive reference ink after about 14 days at 37° C. The“reference” ink was Gotham Ink's “Gotham baseline lavender”, asolvent-based flexographic ink adjusted to obtain an exact color matchwith the indicator ink by adding suitable quantities of Gotham Seriesopaque white, magenta, and cyan inks. This cumulative heat indicator wasintended to have similar appearance and time/temperature response toTemptime's HEATmarker® VVM14 indicator.

VVM14-like indicators that were printed on clear film were placed oversamples of Temptime's DEGmarker® 40 indicators and taped on the edgesonto white card stock (176 g/m², 8.5 by 11 inches Staples White CardStock acid free code #733350). Because the active ink is nearlytransparent when printed on clear film, the gray center dot of theDEGmarker 40 indicators could easily be seen through the active inksquare of the VVM14-like indicators. For comparison, the VVM14-likeindicators and the DEGmarker indicators were also included on the card.

The test card with the indicators were placed inside an oven (BoekelScientific CCC1.4d thermal Incubator), at 25° C., 35° C., 45° C. andheld for 5 minutes at each temperature. Optical density (OD) wasmeasured for the active part of each indicator after each 5-minuteperiod using an X-rite 504 Spectrodensitometer and reported for cyan.There was no change of the indicators at 25° C. and 35° C. At 45° C.,color change of the dual heat indicator and the DEGmarker indicator wasrapid and noticeable and occurred within 2 minutes. The measured opticaldensities may be seen in FIG. 16. FIG. 17 shows the test card with theindicators at no heating and heating at 45° C.

A second set of experiments were performed where dual heat indicatorprototypes were made and placed into heat sealed clear plastic bags sothat they could be observed at increments of 1° C. changes in acirculating water bath (Thermo Scientific AC150 containing 60/40water/propylene glycol). Each sample was placed into the bath at thespecified temperature for 5 minutes. Observations were made at about 2minute intervals by looking into the bath at the samples in the clearplastic bags. OD measurements were not taken. One set of samples wasmade with DEGmarker 40 threshold indicators, and another set was made inthe same way with DEGmarker 45 threshold indicators. Dual heat indicatorprototypes made with VVM14 and either DEGmarker 40 or DEGmarker 45 gaveresponses within a degree or two of the 40° C. and 45° C. respectively.Where color changes were seen, they occurred within 2 minutes ofexposure. Since the response of the DEGmarker was seen through theactive ink “window” of the VVM printed on clear film when made into thedual heat indicator construction, this construction could be a used as adual heat indicator according to FIG. 7. A comparison of the colorappearance of the active region between the dual indicator prototypesmade with VVM14 and either DEGmarker 40 or DEGmarker 45 at the varyingtemperatures may be seen in FIG. 18. The results show how effective thedual heat indicator prototypes are at lower temperatures in comparisonto a cumulative indicator only or peak indicator alone.

Example 3: Demonstration of Peak Indicator with Meltable Activator at aTemperature Above the Activator Melting Point as Illustrated in FIG. 5

Ultratherm product number 004188 is a white direct thermal paper labelstock from Wausau Paper, Wausau Wis., with an initial static thermalsensitivity of 75° C. The static sensitivity is a measurement of thetemperature at which the reaction of the thermal layer sets in. Initialstatic thermal temperature is the temperature at which the thermalcoating develops an optical density of 0.2 OD units. If thermal paper isused to provide the peak indicator component of a dual indicator, thenthe initial static sensitivity temperature represents the lower end ofthe peak indicator response temperature range.

To demonstrate a peak indicator for use in a dual function heatindicator construction, a small amount of ground crystallinebenzophenone (product B9300 from Sigma-Aldrich, St. Louis Mo.) wasspread thinly onto the printable surface of Ultratherm 004188. Themelting point of benzophenone reported by the supplier is 48-49° C. Thiswas placed in an oven at about 50° C. The coating developed black colorin less than 90 seconds where the crystals had been. The remainder ofthe paper remained white. The benzophenone appeared to have melted andpenetrated the thermal coating in the areas of black color. Developmentof the paper by the activator occurred at a temperature much lower thanthe development temperature of the paper itself, and higher than themelting point of the meltable activator.

Example 4: Peak Indicator with Meltable Activator and Substrate at aTemperature Below the Activator Melting Point

Four direct thermal substrates were used for the next example of peakindicators for use in dual function heat indicator constructions. Thethermal substrates were pairs of similar construction except that one ofeach pair was supplied with an additional thin transparent protectivecoating to improve durability and scratch resistance. Samples ofactivator with substrates were prepared in the same manner as forExample 3. Temperature exposure experiments were conducted by puttingtest samples in plastic bags, excluding air so each side of thesubstrate was against the side of the bag, and then immersing this intoa thermostatically controlled water bath (Neslab RTE 17 fromThermoElectron Corp.) at 43° C. Temperature was measured with a mercurythermometer with accuracy of <0.1° C. The samples were observedperiodically for color development and the test ended after 40 minutes.FIG. 19 lists the samples, their static thermal sensitivities, as statedby the manufacturer, and the response to contact with the activator.

In all cases benzophenone crystals were visible, and there was noevidence of melting. Yet, when benzophenone was in direct contact withthe mixture of materials making up the thermal coating there was colordevelopment around the point of contact. The coated samples showedlittle or no development. By inspection with a microscope it was seenthat the development spots for the coated samples were often associatedwith artifacts in the thermal coating, such as protruding fibers, whichare well known to be weak points for barrier coatings, and to be coveredby very little coating, or none at all. Where it was intact, the coatingappeared to act as a barrier between the activator and the thermalcoating.

Example 5: Peak Indicator with Meltable Activator and Substrates withProtective Coating at a Temperature Below and Above the Melting Point

The two direct thermal substrates with protective coatings used forsamples 113 and 115 in Example 4 were used in this example.

Samples of activator with substrates were prepared in the same manner asfor Example 3, and temperature exposure experiments were conducted inthe same manner as for Example 4 except that initial temperature was 35°C. The temperature was increased in small steps over the course ofseveral hours. There was no development in these examples after 10minutes at 44.0° C. The first sign of development was a single spot seen44.5° C. for sample 113A after 10 minutes. After 20 minutes at 45.0° C.sample 115A, also showed a single development spot. Development in bothsamples continued during a 10 minute period at 45.5° C. Extensivedevelopment was seen for sample 113A after a 10 minute dwell at 46.0° C.and for sample 115A after a further 10 min at 46.5° C. At thistemperature it as observed that the benzophenone crystals had melted anddeveloped each example in the adjacent region. Again, the developmentoccurred at temperatures much lower than the static sensitivity of thethermal substrate.

The melting point of the benzophenone used for the above examples wasdetermined separately in the apparatus but with the crystals between twoglass microscope cover slips, again inside a polyethylene bag. Thestarting temperature was 45.0° C. and temperature steps were 0.1° C. inroughly 3 minute intervals. The benzophenone melted at 46.1° C.

In this example the development of the thermal composition occurred attemperatures much lower than the static sensitivity temperature of thethermal substrates but also similarly close to the melting point of themeltable activator, even though the thermal substrates have differentthermal sensitivities. The difference between the temperature wheredevelopment was prevented by the transparent barrier coating and whereit proceeded rapidly was not more than two degrees. This exampleembodiment of a coated thermal substrate and a meltable activator hasdemonstrated a specific response temperature, stability at temperatureslower than but close to the response temperature, and rapid high visualresponse from a small temperature transition through the responsetemperature.

Disclosures Incorporated.

The entire disclosure of each United States patent, each United Statespatent application, each international patent publication, each foreignpatent publication, any other publication, and of each unpublishedpatent application identified in this specification is incorporated byreference herein, in its entirety, for all purposes. Should a conflictappear to be present between the meaning of a term employed in thedescription of the example embodiment of the invention in thisspecification and the usage of the term in material incorporated byreference from another document, the meaning of the term as used hereinis intended to prevail. Any reference to an “example embodiment of theinvention” in any incorporated disclosure is to be understood to referto the example embodiment of the invention described, or claimed, in theincorporated disclosure.

About the Description.

The detailed description herein is to be read in light of and incombination with the descriptions of the background to the exampleembodiment of the invention and of the brief summary of the exampleembodiment of the invention where information regarding the writtendescription of the example embodiment of the invention, the best mode ofpracticing the example embodiment of the invention, or description ofmodifications, alternatives or other useful embodiments of the exampleembodiment of the invention may also be set forth explicitly, orimplied, as will be apparent to one skilled in the art.

The terms “include,” “have,” “has,” and “contain,” and their variousgrammatical forms, are to be understood as being open-ended and not toexclude additional, unrecited elements or method steps.

Throughout the description, where compositions instruments, devicesapparatus, systems, or processes are described as having, including, orcomprising specific components or elements, or in the case of processes,specific steps, it is contemplated that compositions instruments,devices apparatus, systems, or processes according to the presentexample embodiment of the invention may also consist essentially of, orconsist of, the recited components, elements or steps.

In this application, where an element or component is said to beincluded in and/or selected from a list or group of recited elements orcomponents, it should be understood that the element or component may beany one of the recited elements or components, or may be selected from agroup consisting of two or more of the recited elements or components.

The use of the singular herein is intended to include the plural (andvice versa) unless the context indicates otherwise.

Also, where the term “about”, “approximate”, “approximately”, or asimilar term, is used before a quantitative value, the specificquantitative value itself is to be understood to be included, and to beexplicitly recited, unless the description specifically statesotherwise.

With regard to processes, it is to be understood that the order of stepsor order for performing certain actions is immaterial so long as thedescribed process remains operable. Moreover, two or more steps oractions may be conducted simultaneously, unless the context indicatesotherwise. In addition, any proportions recited herein are to beunderstood to be proportions by weight, based upon the weight of therelevant composition, unless the context indicates otherwise. Also,unless the context indicates otherwise, or suggests otherwise, anymethods according to the example embodiment of the invention that aredescribed herein, or one or more steps of the methods, may be practicedat a room temperature in the range of about 20° C. to about 25° C.

The description of the background of the example embodiment of theinvention herein may include insights, discoveries, understandings ordisclosures, or associations together of disclosures, that were notknown in the relevant art prior to the present example embodiment of theinvention but which are provided by the example embodiment of theinvention, and are to be considered elements of the example embodimentof the invention. Some such contributions of the example embodiment ofthe invention may have been specifically pointed out as beingattributable to the example embodiment of the invention, and other suchcontributions of the example embodiment of the invention will beapparent from their context. Merely because a document may have beencited in this application, no admission is made that the field of thedocument, which may be quite different from that of the exampleembodiment of the invention, is analogous to the field or fields of thepresent example embodiment of the invention.

The description of the example embodiment of the invention herein is tobe understood as including combinations of the various elements of theexample embodiment of the invention, and of their disclosed or suggestedalternatives, including alternatives disclosed, implied or suggested inany one or more of the various methods, products, compositions, systems,apparatus, instruments, aspects, embodiments, examples described in thespecification or drawings, if any, and to include any other written orillustrated combination or grouping of elements of the exampleembodiment of the invention or of the possible practice of the exampleembodiment of the invention, except for groups or combinations ofelements that are incompatible with, or contrary to the purposes of theexample embodiment of the invention, as will be, or become, apparent toa person of ordinary skill. Further, embodiments of the exampleembodiment of the invention may have any configuration according to theexample embodiment of the invention that is described herein, or isshown in any accompanying drawings, and may employ any compatible onesof the useful materials or structures described herein.

SCOPE OF THE EXAMPLE EMBODIMENT OF THE INVENTION

The present example embodiment of the invention includes the examplesand embodiments described herein and other specific forms of the exampleembodiment of the invention that embody the spirit or essentialcharacteristics of the example embodiment of the invention or of therespective described examples or embodiments. The foregoing examples andembodiments are in all respects intended to be illustrative of theexample embodiment of the invention described herein. It is to beunderstood that many and various modifications of the example embodimentof the invention, or of an example or embodiment of the exampleembodiment of the invention described herein will be apparent to thoseof ordinary skill in the relevant art, or may become apparent as the artdevelops, in the light of the foregoing description. Such modificationsare contemplated as being within the spirit and scope of the exampleembodiment of the invention or example embodiment of the inventionsdisclosed herein.

We claim:
 1. A dual-function heat indicator for monitoring cumulativeambient heat exposure and peak ambient heat exposure, the dual-functionheat indicator comprising: a cumulative exposure indicator configured tochange in visual appearance in response to a predetermined cumulativeheat exposure; a transparent or translucent peak exposure indicatorcomprising a meltable solid configured to scatter light and melt inresponse to a predetermined peak heat exposure, wherein, in response tothe melting of the meltable solid the light scattering ceases causing adarkening of the peak exposure indicator, the darkening persisting afterthe meltable solid re-solidifies; and a substrate supporting thecumulative and peak exposure indicators in a viewable layeredconfiguration with the cumulative exposure indicator viewable throughthe peak exposure indicator; wherein the cumulative exposure indicatoris functionally separate from the peak exposure indicator.
 2. Thedual-function heat indicator of claim 1, wherein the cumulative heatexposure change in visual appearance is irreversible and occurs afterthe predetermined cumulative heat exposure.
 3. The dual-function heatindicator of claim 2, wherein the predetermined cumulative heat exposureis a temperature of at least about 37° C. lasting for about 30 days. 4.The dual-function heat indicator of claim 1, wherein the substrate isblue or gray.
 5. The dual-function heat indicator of claim 1, furthercomprising a thermochromic ink coated on the substrate.
 6. Thedual-function heat indicator of claim 1, wherein the meltable solid ofthe peak exposure indicator is a particulate meltable solid suspended ina binder material, wherein air gaps are present between particles of themeltable solid.
 7. The dual-function heat indicator of claim 1, whereinthe meltable solid comprises a side-chain crystalline polymer.
 8. Thedual-function heat indicator of claim 1, wherein the meltable solidcomprises a meltable polymer and a dye, wherein melting of the polymerin response to the predetermined peak heat exposure reveals a color ofthe dye.
 9. The dual-function heat indicator of claim 1, wherein themeltable solid comprises meltable particulate colored material, whereinmelting of the meltable solid in response to the predetermined peak heatexposure reveals an inherent color of the colored material.
 10. Thedual-function heat indicator of claim 1, wherein the substrate furthercomprises a first layer, the cumulative exposure indicator furthercomprises a second layer adjacent the first layer, and the peak exposureindicator further comprise a third layer adjacent the second layer. 11.The dual-function heat indicator of claim 1, wherein the cumulativeexposure indicator comprises a material that is removed or dissolvedover time with exposure to heat.
 12. The dual-function heat indicator ofclaim 11, wherein the material is removed by an acid or a base thatreacts with the material at a predictable rate.
 13. The dual-functionheat indicator of claim 1, further comprising an adhesive layerpositioned against the substrate.
 14. The dual-function heat indicatorof claim 13, further comprising a release liner positioned against theadhesive layer.
 15. The dual-function heat indicator of claim 1, furthercomprising a transparent film positioned between the meltable solid andthe cumulative exposure indicator.
 16. The dual-function heat indicatorof claim 1, wherein the cumulative exposure indicator comprises adiacetylenic compound.
 17. The dual-function heat indicator of claim 1,wherein the cumulative exposure indicator comprises a layer of aluminumand an etchant configured to etch away the aluminum over time responsiveto exposure to heat over time so as to reveal the underlying substrate.18. The dual-function heat indicator of claim 17, wherein the cumulativeexposure indicator further comprises a barrier coating configured toinitially separate the etchant from the layer of aluminum and to controla rate at which the etchant reacts with the layer of aluminum.
 19. Thedual-function heat indicator of claim 17, further comprising apressure-sensitive laminating adhesive layer containing the etchant. 20.The dual-function heat indicator of claim 17, wherein the etchant isselected from a group consisting of nitric acid, hydrochloric acid,picric acid, ethanol, potassium hydroxide, copper sulfate, sodiumthiosulfate, potassium metabisulfite, copper chlorite, copper chlorate,copper ammonium, ammonia, hydrogen peroxide, hydrofluoric acid,phosphoric acid, and mixtures thereof.
 21. An article of manufacture,comprising: a perishable host product; a package containing theperishable host product; and a dual-function heat indictor of claim 1 inor on the package.